Tetrasubstituted Furans by Nucleophile-Induced Cleavage of Carbonyl Ylide-DMAD Cycloadducts

Article abstract of DOI:10.1055/s-0040-1707897

Compounds incorporating a 4-aza-8-oxabicyclo[3.2.1]oct-6-en-2-one moiety, which were prepared by a tandem carbenoid carbonyl ylide cyclization/[3+2]-cycloaddition reaction from ethyl 2-diazo-3-oxo-4-phthalimidobutanoates, undergo a nucleophile-induced two-bond ring cleavage when treated with protic heteronucleophiles. In this manner, tetrasubstituted furantricarboxylates, tethered with α-amino acids, esters, thioesters, and amides by a 2-carbonylphenyl moiety, are obtained.

Full text of DOI:10.1055/s-0040-1707897

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2020, 52, A–N
paper
A
en
Synthesis
M. Dobesch et al.
Paper
Tetrasubstituted Furans by Nucleophile-Induced Cleavage of
Carbonyl Ylide–DMAD Cycloadducts
Matthias Dobesch1
COOMe
COOEt
COOMe
MeOOC
MeOOC
Julian Greiner
COOEt
O
Gerhard Maas*
0
0
0
0-0
0
0
2-9
2
8
9-
4
2
1
0
O
Nu-H
O
O
N
H
Institute of Organic Chemistry I, Ulm University,
Albert-Einstein-Allee 11, 89081 Ulm, Germany
gerhard.maas@uni-ulm.de
N
Nu
R
O
O
R
cat. Rh2(OAc)4
DMAD
R = H, Me, i-Pr
O
–
+
O
Nu-H = H2O, ROH, RS /H ,
NH3, 1° and 2° amines
N
COOEt
O
R
N2
Received: 06.05.2020
Accepted after revision: 27.05.2020
Published online: 20.07.2020
ylenes.9–15 Since the resulting bi- or polycyclic cycloadducts
contain a 2,5-dihydrofuran moiety, we saw opportunities to
convert the latter into a non-bridged furan ring.
DOI: 10.1055/s-0040-1707897; Art ID: ss-2020-t0238-op
In fact, it has been reported that the carbonyl ylide–
DMAD adduct 1 undergoes an easy thermal [4+2] cyclorev-
ersion into a furan and an isocyanate moiety (Scheme 1);
this reactivity appears not to be induced by ring strain,
Abstract Compounds incorporating a 4-aza-8-oxabicyclo[3.2.1]oct-6-
en-2-one moiety, which were prepared by a tandem carbenoid carbon-
yl ylide cyclization/[3+2]-cycloaddition reaction from ethyl 2-diazo-3-
oxo-4-phthalimidobutanoates, undergo a nucleophile-induced two-
bond ring cleavage when treated with protic heteronucleophiles. In this
manner, tetrasubstituted furantricarboxylates, tethered with -amino
acids, esters, thioesters, and amides by a 2-carbonylphenyl moiety, are
obtained.
since an analogous reaction occurs when no cycloalkane
10a
annulation is present.
In another study, the 8-oxabicy-
clo[3.2.1]oct-6-en-2-one derivative 2 could be converted
into a 2-arylfuran-3,4-dicarboxylate in two photochemical
steps.16
Key words diazo compounds, carbonyl ylides, carboxamides, cycload-
dition, furan
Padwa et al. (1989)
The tandem carbonyl ylide formation/[3+2] cycloaddi-
tion reaction is an interesting strategy for the fast construc-
tion of molecular complexity from structurally simple pre-
cursors. Carbonyl ylides are reactive 1,3-dipoles, which are
usually generated and trapped in situ by inter- or intramo-
lecular [3+2] cycloaddition with suitable alkenes, alkynes,
and other -bond systems. In this manner, cyclic carbon-
yl ylides allow the preparation of bicyclic structures incor-
porating an oxygen bridge, which in turn provide an access
to a wide range of (poly)cyclic natural and non-natural
MeOOC
COOMe
O
MeOOC
COOMe
O
Δ
O
[
4+2] cycloreversion
O
n
N
n
O
N
C
O
1
Padwa et al. (1991)
1–3
MeO
MeO
O
COOMe
COOMe
MeOOC
COOMe
hν
hν
O
COOMe
COOMe
O
O
1
,4–7
products.
While carbonyl ylides are most often generat-
O
2
COOMe
1–3,7
ed from diazocarbonyl compounds,
other approaches
1,4
This work
MeOOC
also exist, including the recently reported Rh(II)-cata-
lyzed dediazotization of 1-sulfonyl-1,2,3-triazoles (bearing
a carbonyl-containing substituent at C-4) followed by
COOMe
COOEt
COOMe
MeOOC
COOEt
O
Nu−H
metallocarbenoid intramolecular carbonyl ylide formation
O
O
O
and 1,3-dipolar cycloaddition.8
N
H
N
R
Nu
Quite a number of carbonyl ylides, which were generat-
ed from -diazocarbonyl compounds, have been trapped
with acetylenic dipolarophiles, such as dimethyl acetyl-
enedicarboxylate (DMAD), alkyl propynoates, and arylacet-
O
3
O
R
R = H, Me, i-Pr
Scheme 1 Furan synthesis from carbonyl ylide–DMAD cycloadducts
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
M. Dobesch et al.
Paper
Herein we report on the two-bond cleavage of the oxa-
bicyclooctene substructure of 3 using protic heteronucleo-
philes (Scheme 1); this transformation generates highly
functionalized 5-(ortho-substituted aryl)furan-2,3,4-tricar-
boxylates. The interest in the synthesis of multiply substi-
tuted furans is ongoing. Classical approaches, such as cyclo-
condensation, cycloisomerization, and ring substitution,
librium was detected in wet DMSO solution.14a In contrast,
3a and 3b in an acetone/water solution readily undergo a
two-bond cleavage leading to carboxylic acids 5a and 5b,
respectively (Scheme 3). The higher reaction temperature
for 3a compared to 3b was chosen to achieve complete solu-
bility of 3a in aqueous acetone. On the other hand, isopro-
pyl-substituted 3c reacted with water only sluggishly; in re-
fluxing aqueous acetone, a low conversion was observed
even after 64 h (NMR control) and full conversion accompa-
nied by extensive formation of undefined byproducts in
aqueous 1,4-dioxane at 90 °C after 19 days. In contrast to
the clean hydrolysis at neutral pH, exposure of 3b to an
17
and novel modifications thereof have recently been com-
plemented in particular by novel transition-metal-cata-
18,19
lyzed strategies.
Moreover, several new, metal-free ap-
proaches to tetrasubstituted furan-3,4-dicarboxylates have
20,21
been published in recent years.
This study was carried out with the carbonyl ylide–
DMAD cycloaddition products 3a–c, which were prepared
from 2-diazo-3-oxo-4-phthalimidobutanoic esters 4 as out-
equimolar amount of aqueous NaOH or NaHCO led to un-
specific decomposition.
3
14a
COOMe
lined in Scheme 2. Syntheses of 3b and of the carbonyl
COOMe
MeOOC
10b
MeOOC
ylide precursor of 3a along these lines have already been
published. While the methyl derivative 3b was obtained as
a mixture of diastereomers (exo-Me/endo-Me 2:1), only the
exo-isopropyl isomer of 3c was obtained, as was confirmed
by an XRD structure determination (Figure 1). In the course
of our work, it turned out that the carbonyl reactivity of 3a–
c markedly depended on the steric demand of the adjacent
substituent R.
COOEt
COOEt
2
H O
O
O
O
O
H
N
N
OH
R
O
O
R
3
5
a: R = H: acetone/H2O, 40 °C, 5 min; 73% yield of 5a
b: R = Me (exo/endo = 2:1): acetone/H2O, 20 °C, 5 min; 72% yield of 5b
c: R = exo-i-Pr: 1,4-dioxane/H2O, 90 °C, 19 d; impure 5c
Scheme 3 Reaction of 3a–c with water
R
CO2H
O
COOMe
COOEt
Encouraged by the smooth hydrolytic cleavage of 3a,b,
we became interested in analogous transformations using
other protic heteronucleophiles. Scope and limitations of
the reaction of 3a–c with aliphatic alcohols can be seen in
Table 1. As for the hydrolysis reaction, the success of the re-
action with alcohols obviously depends very much on steric
factors. Thus, the reactivity toward methanol, as the sim-
plest alcohol, clearly decreases in the order 3a > 3b > 3c (en-
MeOOC
O
N
O
O
iii
N2
O
i,ii
N
COOEt
–
O
N
O
R
N2
R
O
4
3
a: R = H; b: R = Me; c: R = i-Pr
Scheme 2 Preparation of 4-aza-8-oxabicyclo[3.2.1]octen-2-ones 3
used in this study. Reagents and conditions: (i) 1. phthalic anhydride, -
amino acid, NEt , toluene; 2. CDI, then CH (COOEt)COOH, NEt , anhyd
MgCl ; (ii) imidazole-1-sulfonyl azide·HCl, NEt ; (iii) Rh (OAc) (3 mol%),
DMAD, benzene, 80 °C (yield: 53–76%). CDI = 1,1′-carbonyldiimidazole.
3
2
3
COOMe
COOMe
COOEt
2
3
2
4
MeOOC
COOMe
COOEt
COOEt
MeOH
MeOOC
O
MeOOC
O
O
+
O
N
20 °C
0 min
O
H
N
3
O
Me
N
O
OMe
3
b
O
Me
Me
endo-3b
COOMe
MeOOC
O
(exo-Me/endo-Me = 2:1)
6b
COOEt
O
MeOH
65 °C, several h
MeOH
5 °C, 30 min
O
N
6
COOMe
O
MeOOC
COOMe
O
O
H
N
OMe
COOMe
COOMe
O
7
b
MeOOC
Figure 1 Solid-state molecular structure of exo-isopropyl-3c (ORTEP
plot)
MeOH
0 °C, 40 h
2
O
3c
6c
+
O
H
N
OMe
We have observed earlier, that the keto group of a car-
bonyl ylide–N-phenylmaleimide cycloadduct, structurally
analogous to 3, is easily hydrated and a keto/gem-diol equi-
O
7c
Scheme 4 Reaction of 3b with methanol
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

C
Synthesis
M. Dobesch et al.
Paper
tries 1–4). Moreover, a closer inspection of the methanoly-
sis of alanine-derived 3b revealed that exo-3b reacted faster
than endo-3b at room temperature (Scheme 4). The latter
diastereomer (clearly identified by an XRD diffraction anal-
By the way, the latter fact allowed to recrystallize 3b
and 3c from i-PrOH in the preparation procedure. Finally,
even the sterically least biased tetracycle 3a did not react
with t-BuOH (entry 10).
In contrast to aliphatic alcohols, neutral SH compounds
did not react with tetracycles 3. In the presence of an ap-
propriate base, however, 3b reacted smoothly with thio-
phenolate or cyclohexanethiolate to afford thioesters 8a,b
(Scheme 5).
14a
ysis ), as well as the diastereomeric mixture of 3b, were
readily and completely converted into 6b in refluxing meth-
anol. Prolonged heating of 6b in methanol led to a transes-
terification equilibrium mixture of 6b and tetramethyl tet-
racarboxylate 7b. In a very slow reaction, valine-derived 3c
reacted with methanol at room temperature to give a mix-
ture of 6c and transesterification product 7c, which, how-
ever, could not be separated. Extended heating of this mix-
ture in hot methanol converted 6c into 7c accompanied by
decomposition products, which could not be removed.
Higher primary aliphatic alcohols, benzyl and allyl alco-
hol also reacted in good yields with 3a and 3b (Table 1, en-
tries 5–7, 11–14), but again the retarding effect of substitu-
ent R could be noted (entries 5/6 and 11/12). The limit was
reached when -branched aliphatic alcohols were applied:
when glycine-derived 3a was exposed to i-PrOH, the nucle-
ophilic ring cleavage reaction was still achieved in fair yield
COOMe
R'−SH, base
CH2Cl2
r.t., 30 min
MeOOC
COOEt
O
3b
O
H
(
exo/endo = 2)
N
SR'
O
R = Ph, base = NEt3: 8a (69%)
R = cyclohexyl, base = DBU: 8b (66%)
Scheme 5 Ring cleavage of 3b with thiolates
We were pleased to find that the nucleophilic ring
cleavage of tetracycles 3a–c could also be achieved with a
wide range of amines (ammonia, primary and secondary al-
(albeit with thermal activation, entry 8), but no reaction
occurred in the case of alanine-derived 3b (entry 9).
Table 1 Reaction of 3a–c with Alcoholsa
COOMe
MeOOC
COOMe
MeOOC
COOEt
COOEt
R'OH
O
O
O
O
H
N
N
OR'
R
O
O
R
3a–c
6
Entry
Substrate
R
Solvent/R′OH
T (°C)
Time
0.5 h
Product
Yield (%)
72
1
2
3a
3b
H
CH
2
2
Cl
2
/MeOH
/MeOH
20
20
6a
Me
CH
Cl
2
0.5 h
6b
endo-3b
48
38
3
4
5
6
7
8
9
3b
3c
3b
3c
3b
3a
3b
3a
3a
3b
3a
3a
Me
i-Pr
Me
i-Pr
Me
H
MeOH
MeOH
EtOH
65
0.5 h
40 h
6 h
6b
79
20
6c and 7cb
78
6d
76
EtOH
70
230 h
6 h
6ec
PrOH
90
6f
80
69
i-PrOH
i-PrOH
82
8 h
6g
Me
H
82
20 h
20 h
6 h
no reaction
10
11
12
13
14
t-BuOH
reflux
65
no reaction
H
BnOH
6h
6i
68
62
71
67
Me
H
BnOH
100
95
12 h
6 h
hex-5-en-1-ol
6j
H
CH
2
=CHCH
2
OH
85
6 h
6k
a
Cycloadduct 3b (R = Me) was used as a diastereomeric mixture (exo/endo 2:1), 3c (R = i-Pr) as the exo isomer.
Complete conversion into a 3:1 mixture of 6c and 7c; subsequent heating at 65 °C for 112 h afforded transesterification product 7c and unidentified decompo-
b
sition products.
c
Unidentified decomposition products could not be removed.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

D
Synthesis
M. Dobesch et al.
Paper
iphatic amines, anilines) (Scheme 6) and furnished tetra-
substituted furans 9 tethered with -amino acid amide
moieties. The majority of the reactions were completed
within 5–10 minutes, including those with sterically more
demanding -branched amines (tert-butylamine, cyclohex-
preparation of 9n (from Gly-OMe) and 9o (from NH -Met-
2
Gly-OMe) suggests, that other amino acid and peptide de-
rivatives decorated with these tetrasubstituted furan moi-
eties can also be prepared.
A mechanistic proposal for the reported nucleophilic
two-bond cleavage reactions of tetracycles 3 is outlined in
Scheme 7. The transformation very likely begins with an
addition of the protic nucleophile (or the thiolate anion in
the case of RSH/base) to the keto group of the -keto ester
moiety of 3. In contrast to the N-phenylmaleimide cycload-
duct analogous to 3, for which we have observed an equilib-
rium between the keto and the gem-diol form,1 tetrahe-
dral carbonyl addition products 10 appear to undergo a
spontaneous fragmentation, which can be considered as a
ylamine, methyl piperidine-4-carboxylate, and H N-Met-
2
Gly-OMe) and the less nucleophilic 4-bromoaniline. The re-
actions leading to 9d (CH Cl , 40 °C, 16 h, 51% yield), 9h
2
2
(
EtOAc, 20 °C, 40 h, 57%) and 9j (CH Cl , 20 °C, 40 h, 70%)
2 2
proceeded more reluctantly. In the first two cases, this can
be attributed to the steric influence exerted by the isopropyl
substituent of 3c, in the third case to the low nucleophilici-
ty of 4-nitroaniline.
Gratifyingly, amines carrying additional functional
groups can also be applied, allowing the preparation of
multiply functionalized molecular structures. One such ex-
ample is the N-(3-azidopropyl)carboxamide 9k, which was
further transformed into 1,2,3-triazole 9l by a [3+2] cy-
cloaddition reaction with DMAD (83% yield). The successful
4a
variation of the retroaldol reaction of -hydroxycarbonyl
compounds.2
2,23
Thus, 10 could undergo OH deprotonation
followed by cleavage of the adjacent C–C bond and extend-
ed bond reorganization with delocalization of the negative
charge as shown by intermediate structure (a). However,
COOMe
MeOOC
COOMe
MeOOC
COOEt
COOEt
1
2
HNR R
O
O
O
O
51−93%
H
N
N
1
2
NR R
R
O
O
R
3
3
3
a: R = H
b: R = Me (exo/endo = 2:1)
c: R = exo-i-Pr
9
COOMe
COOMe
MeOOC
COOMe
COOMe
COOEt
MeOOC
MeOOC
MeOOC
COOEt
O
COOEt
COOEt
O
O
O
O
O
O
O
H
N
H
N
H
N
H
N
NH2
N
Ph
N
H
N
H
H
O
O
R
O
O
9a
9, R = H (b), Me (c), i-Pr (d)
9e
9f
COOMe
COOMe
COOMe
COOEt
COOMe
MeOOC
MeOOC
MeOOC
MeOOC
COOEt
O
COOEt
O
COOEt
O
O
O
O
X
O
O
H
N
H
N
H
H
N
N
N
H
N
H
N
H
N
H
Z
O
O
O
O
9g
9h
9, X = Br (i), NO2 (j)
9k: Z = N3
DMAD
N
N
N
9l: Z =
MeOOC
COOMe
COOMe
COOMe
COOMe
MeOOC
MeOOC
MeOOC
S
COOEt
O
COOEt
O
COOEt
O
O
O
O
H
N
H
N
H
N
H
N
COOMe
N
N
H
COOMe
N
H
O
O
O
O
COOMe
9n
9o
9m
Scheme 6 Ring cleavage of tetracycles 3a–c with amines, and products 9. Reagents and conditions: tetracycle 3 (~0.2–0.5 mmol), amine (moderate
excess), CH Cl , r.t., 5–10 min; see text for exceptions.
2
2
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

E
Synthesis
M. Dobesch et al.
Paper
the retroaldol reaction is in general base-catalyzed, which
cannot apply to the cases where tetracycles 3 were exposed
to water or alcohols. Therefore we propose that the first
step of the fragmentation of 10 is a heterolytic bond fission
resulting in a resonance-stabilized carbocation and relief of
steric strain [see intermediate structure (b)]. In the second
step, the 2,5-elimination at the dihydrofuran ring is com-
pleted as shown.
and 13C), (DMSO-d ) = 2.50 and 39.52, (CD Cl ) = 5.32 and 54.00. 13C
6
2
2
signals were assigned by means of APT, HMBC and HSQC experi-
ments. IR spectra of solids were recorded on a Bruker Vector 22 FT-IR
instrument (solids: KBr pellets or in the ATR mode; oils between NaCl
plates); wavenumbers and relative intensities of selected absorptions
are reported. Mass spectra were recorded with the following instru-
ments: Finnigan MAT SSQ-7000 (CI, 100 eV), Bruker Daltonics Reflex
III (MALDI-TOF), and Bruker solariX (HRMS). Elemental analyses were
carried out with a Heraeus Vario EL or an elementar Hanau vario MI-
CRO cube analyzer. Column chromatography was performed on silica
gel (63–200 mesh). Differental Scanning Calorimetry (DSC) measure-
COOMe
MeOOC
ments were performed on a Perkin Elmer DSC 7 instrument (N at-
2
COOEt
–1
O
mosphere, heating and cooling rates 10 °C min ); glass transition
O
H
temperatures (T ) were taken from the second heating cycle. PE = pe-
g
N
Nu
troleum ether (bp 40–65 °C).
COOMe
COOEt
R
COOMe
COOEt
MeOOC
O
Syntheses of diazo ester 4a10b (here prepared with imidazole-1-sulfo-
MeOOC
(
a)
14a
O
nyl azide as diazo transfer reagent) and 4b, as well as cycloadduct
or
O
H
14a
O
3b, have been published.
O
N
COOMe
COOEt
Nu
MeOOC
N
R
Nu
O
Ethyl 5-Methyl-3-oxo-4-phthalimidohexanoate
−
O
R
O
10
O
H
See Scheme 2. To a solution of N-phthaloyl-DL-valine (20.4 g, 83
mmol) in anhyd THF (200 mL) was added CDI (17.5 g, 108 mmol) in
portions and the mixture was stirred at r.t. for 10 h. In the meantime,
a second round-bottom flask was placed in an ice-water bath, purged
with argon and charged with anhyd THF (120 mL). Hydrogen ethyl
+
N
11
Nu
Nu−H
H+
R
O
3
(
b)
5
, 6, 8, 9
Scheme 7 Proposed mechanism for the nucleophilic two-bond cleav-
age of tetracycles 3
malonate (13.0 mL, 110 mmol), anhyd MgCl (8.1 g, 84 mmol), and
2
dry NEt3 (17.0 mL, 123 mmol) were added. The suspension was
stirred for 2 h at 0 °C, then the two preparations were combined and
allowed to react at 20 °C for 15 h. The solution was concentrated to
about 10% of its original volume and Et O was added. After extraction
A certain analogy of the 2,5-elimination is given by the
conversion of a 5-methoxy-2,5-dihydrofuran-2-carboxylic
ester into a furan devoid of the two substituents upon treat-
ment with methanolic KOH. In this instance, a nucleophilic
attack at the ester group initiates the fragmentation pro-
2
with water (3 ×) and re-extraction of the aqueous phases with Et O,
2
all organic phases were combined and dried (Na SO ) and the vola-
2
4
tiles were evaporated. The residual yellow oil (27.8 g) could not be pu-
rified completely.
IR (NaCl): 1614 (w), 1720 cm–1 (s).
24
cess.
1
3
H NMR (CDCl , 400 MHz):  = 0.78 (d, J = 6.8 Hz, 3 H, CHMe), 1.02 (d,
3
In conclusion, we have found that the 4-aza-8-oxabicyc-
lo[3.2.0]hept-6-en-2-one substructure, which is part of the
tetracyclic carbonyl ylide–DMAD cycloadducts 3, can un-
dergo a two-bond cleavage induced by protic heteronucleo-
philes. While this transformation results in the breakdown
of the tetracyclic framework, it generates densely function-
alized products, namely tetrasubstituted furans that are
tethered with -amino acids (or their esters and amides) by
a carbonylphenyl moiety. In particular, primary and sec-
ondary amines are versatile reagents for this transforma-
tion, because their nucleophilicity can vary over a broad
range, steric factors appear to be less important than in the
case of alcohols, and functionalized amines can be used to
introduce additional functional groups.
3
3
J = 6.6 Hz, 3 H, CHMe), 1.11 (t, J = 7.1 Hz, 3 H, OCH Me), 2.69–2.75
2
2
(m, 1 H, CHMe ), 3.33 and 3.45 (AB d, J = 15.7 Hz, 2 H, COCH CO),
2
2
3
3
.99–4.06 (m, 2 H, OCH Me), 4.56 (d, J = 8.1 Hz, 1 H, NCH), 7.73–7.77
2
(m, 2 H, H ), 7.84–7.88 (m, 2 H, H ); signals of the enol tautomer (8–
Ar
Ar
9% by integration):  = 5.32 (s, HO–C=CH), 12.09 (s, C–OH).
13
C NMR (CDCl , 101 MHz):  = 13.81 (OCH Me), 18.79 and 20.68
3
2
(CHMe
), 27.13 (CHMe
), 46.73 (COCH
CO), 61.41 (OCH Me), 63.48
2
2
2
2
(
NCH), 123.65 (CH ), 131.31 (C ), 134.46 (CH ), 166.46 (COOEt),
Ar
q
Ar
167.70 (NC=O), 196.65 (CHC=O).
+
MS (CI): [M] calcd for C17H NO : 317.34; m/z = 318 [M + H] , 272 [M
19
5
+
+
–
OEt] , 202 [M – COCH COOEt] .
2
Ethyl 2-Diazo-5-methyl-3-oxo-4-phthalimidohexanoate (4c)
Imidazole-1-sulfonyl azide hydrochloride (4.8 g, 23 mmol) and anhyd
NEt3 (11.0 mL, 79 mmol) were added to a solution of crude ethyl 5-
methyl-3-oxo-4-phthalimidohexanoate (5.1 g, 16.0 mmol) in anhyd
CH Cl (250 mL), and the mixture was heated with stirring at reflux
2
2
Solvents were dried by established procedures and stored over molec-
ular sieves (4 Å; 3 Å for MeOH). Melting points were determined in
open capillaries with a Büchi B-540 instrument at a heating rate of
during 14 h. After cooling, the red solution was extracted with dilute
1 M aq HCl (2 ×), then with water. The organic layer was separated,
dried (Na SO ), filtered, and concentrated. Purification by column
2
4
2
°C/min. NMR spectra were recorded on a Bruker DRX 400 spectrom-
chromatography (silica gel, cyclohexane/Et O, 1:1) afforded 4c (3.1 g,
56%) as a yellow oil.
IR (NaCl): 2144 (w), 1725 (s), 1266 cm–1 (vs).
2
1
13
eter ( H: 400.13 MHz; C: 100.61 MHz) and on a Bruker Avance 500
spectrometer ( H: 500.16 MHz; C: 125.76 MHz) and were calibrated
based on the residual solvent signal: (CDCl ) = 7.26 and 77.00 ( H
1
13
1
3
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

F
Synthesis
M. Dobesch et al.
Paper
1
3
H NMR (CDCl , 400 MHz):  = 0.92 (d, J = 6.9 Hz, 3 H, CHMe), 1.06 (d,
IR (KBr): 1007 (m), 1276 (s), 1322 (s), 1374 (s), 1707 (s), 1725 (m),
1760 (s), 3435 cm (br).
3
3
3
–1
J = 6.7 Hz, 3 H, CHMe), 1.18 (t, J = 7.1 Hz, 3 H, OCH Me), 2.81–2.95
2
3
(m, 1 H, CHMe ), 4.09–4.23 (m, 2 H, OCH Me), 5.21 (d, J = 8.6 Hz, 1 H,
1
3
2
2
H NMR (CDCl , 400 MHz):  = 0.91 (d, J = 7.0 Hz, 3 H, CH CHMe),
3 3
NCH), 7.67–7.75 (m, 2 H, H ), 7.79–7.88 (m, 2 H, H ).
3
3
Ar
Ar
1.21 (d, J = 7.1 Hz, 3 H, CH CHMe), 1.34 (t, J = 7.1 Hz, 3 H, OCH Me),
3
2
13
C NMR (CDCl , 101 MHz):  = 14.14 (OCH Me), 19.14 and 20.13
3.44–3.56 (m, 4 H, CH CHMe, OMe), 3.92 (s, 3 H, OMe), 4.27–4.47 (m,
3
2
3
3
(CHMe ), 28.00 (CHMe ), 60.71 (NCH), 61.62 (OCH Me), 123.41 (CH ),
2 H, OCH Me), 4.83 (d, J = 3.4 Hz, 1 H, NCH), 7.59–7.70 (m, 3 H, H ),
2
2
2
Ar
2
Ar
1
31.47 (C ), 134.05 (CH ), 160.53 (COOEt), 167.74 (NC=O), 187.06
7.83–7.90 (m, 1 H, HAr).
q
Ar
(
CHC=O); the diazo carbon signal was not observed.
13
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 16.86 and 19.93
3
2
+
+
MS (CI): m/z = 344 [M + H] , 316 [M + H – N ] , 202 [M –
COCN COOEt] .
(CHMe ), 28.72 (CHMe ), 52.95 and 53.37 (OMe), 63.39 (OCH Me),
68.99 (NCH), 93.19 (CHCOCbridgehead), 97.66 (NCbridgehead), 123.53,
2
2
2
2
+
2
1
23.73, 131.43, 132.72 (CH ), 133.87, 137.49, 139.02, 143.09 (C ),
Anal. Calcd for C17H17N O (343.34): C, 59.47; H, 4.99; N, 12.24 (no
correct elemental analysis obtained).
A
r
q
3
5
159.81 (COOMe), 161.66 (COOCH Me), 161.94 (COOMe), 164.85
2
(NC=O), 188.94 (CHC=O).
A preparation of diazo ester 4a from 1a according to this procedure
+
+
+
MS (CI): m/z = 458 [M + H] , 426 [M – OMe] , 398 [M – COOMe] .
afforded a pale orange-colored solid in 80% yield; mp 147–148 °C
10b
(
Lit. 149–150 °C].
Anal. Calcd for C23H23NO (457.44): C, 60.39; H, 5.07; N, 3.06. Found:
9
C, 60.16; H, 5.05; N, 3.12.
Carbonyl Ylide Cycloaddition Products 3
Reactions of Tetracycles 3 with Water
9
7
-Ethyl 10,11-Dimethyl (9RS,11aSR)-9,11a-Epoxy-5,8-dioxo-
,8,9,11a-tetrahydro-5H-azepino[2,1-a]isoindole-9,10,11-tricar-
N-{2-[5-(Ethoxycarbonyl)-3,4-bis(methoxycarbonyl)furan-2-
boxylate (3a)
yl]benzoyl}glycine (5a)
To a solution of diazo ester 4a (900 mg, 3.0 mmol) in dry benzene (14
mL) was added DMAD (0.4 mL, 3.3 mmol) dissolved in benzene (20
mL) and Rh (OAc) (40 mg, 3 mol%). The magnetically stirred mixture
Tetracycle 3a (160 mg, 0.38 mmol) was suspended in a mixture of ac-
etone (5 mL) and water (2 mL). On warming to 40 °C, a clear solution
resulted, which was stirred for 5 min. The solvents were removed in
2
4
was heated at reflux for 6 h, then at r.t. until formation of a green-
colored precipitate had ceased. It was filtered off and, in order to re-
move the green rhodium catalyst, it was triturated with 1 M hydrox-
vacuo and the residue was triturated with Et O (10 mL) in an ultra-
2
sonic bath. The colorless solid was isolated and dried (50 °C/10–3
mbar) to furnish pure 5a (122 mg, 73%); mp 171–172 °C.
IR (KBr): 1184 (s), 1239 (s), 1663 (m), 1729 (s), 3391 cm–1 (br, m).
25
ylamine hydrochloride under ultrasonication. The green-colored
water phase was decanted off and this procedure was repeated, until
the remaining solid product was colorless. It was washed with water
1
3
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, COOCH Me),
3
2
3
–3
3.71 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.13 (d, J = 5.3 Hz, 2 H, NCH ),
4
2
(
2 × 10 mL) and dried (50 °C/10 mbar) to afford 3a (869 mg, 70%) as
3
3
.34 (q, J = 7.1 Hz, 2 H, OCH Me), 6.53 (t, J = 5.1 Hz, 1 H, NH), 7.55–
2
a colorless solid; mp 198–200 °C.
IR (ATR): 1182 (m), 1230 (m), 1282 (m), 1643 (w), 1718 (s), 3278 cm–1
7
.61 (m, 3 H, H ), 7.67–7.73 (m, 1 H, H ).
Ar
Ar
13
C NMR (CDCl , 126 MHz):  = 14.03 (OCH Me), 41.74 (NCH ), 52.24
3
2
2
(br, w).
and 53.06 (OMe), 61.93 (OCH Me), 115.36, 126.03, 126.93 (C ),
2
q
1
3
H NMR (CDCl , 400 MHz):  = 1.33 (t, J = 7.2 Hz, 3 H, OCH Me), 3.61
3
2
127.76, 130.34, 130.82, 131.64 (CH ), 136.10, 140.56 (C ), 157.21
A
r
q
A
B
(s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.29–4.45 (m, 3 H, NCH H ,
(
COOEt), 158.79 (C ), 161.55 and 163.59 (COOMe), 168.20 (NC=O),
q
2
A
B
OCH Me), 4.87 (d, J = 19.6 Hz, 1 H, NCH H ), 7.60–7.72 (m, 3 H, H ),
2
Ar
172.13 (COOH).
7.85–7.92 (m, 1 H, HAr).
+
+
+
MS (CI): m/z = 434 [M + H] , 416 [M – OH] , 402 [M – OCH ] , 359 [M –
3
13
C NMR (CDCl , 101 MHz):  = 13.90 (OCH Me), 48.64 (NCH ), 52.97
+
3
2
2
NHCH COOH] .
2
and 53.35 (OMe), 63.39 (OCH Me), 92.30 (CH COCbridgehead), 97.64 (NC-
2
2
Anal. Calcd for C20H19NO10 (433.37): C, 55.43; H, 4.42; N, 3.23. Found:
C, 55.41; H, 4.64; N, 3.17.
bridgehead), 124.05, 124.18, 131.47 (CH ), 132.29 (C ), 132.88 (CH ),
Ar
q
Ar
1
34.63, 138.90, 143.85 (C ), 159.49 (COOMe), 161.58 (COOEt), 162.06
q
(
COOMe), 165.63 (NC=O), 186.96 (CH C=O).
2
N-{2-[5-(Ethoxycarbonyl)-3,4-bis(methoxycarbonyl)furan-2-
yl]benzoyl}alanine (5b)
+
+
MS (CI): m/z = 416 [M + H] , 356 [M – COOCH ] .
3
Anal. Calcd for C20H17NO (415.35): C, 57.84; H, 4.13; N, 3.37. Found:
C, 57.61; H, 4.14; N, 3.29.
9
The solution of 3b (300 mg, 0.70 mmol) in acetone/water (8 mL/3 mL)
was stirred for 5 min at 20 °C. After evaporation of the volatiles in vac-
uo, the crude product was purified by column chromatography (silica
gel, acetone) to give 5b (227 mg, 72%) as a colorless solid; mp 179 °C.
9
-Ethyl 10,11-Dimethyl (7SR,9SR,11aRS)-9,11a-Epoxy-7-exo-iso-
propyl-5,8-dioxo-7,8,9,11a-tetrahydro-5H-azepino[2,1-a]isoin-
dole-9,10,11-tricarboxylate (3c)
IR (ATR): 1176 (s), 1230 (s), 1647 (m), 1718 (s), 3350 cm–1 (br, w).
1
3
H NMR (CDCl , 400 MHz):  = 1.31 (t, J = 7.1 Hz, 3 H, OCH Me), 1.40
3
2
To a solution of diazo ester 4c (1.80 g, 5.2 mmol) in dry benzene (20
mL) was added DMAD (0.7 mL, 5.7 mmol) dissolved in benzene (40
mL) and Rh (OAc) (77 mg, 3 mol%). The magnetically stirred mixture
was heated at reflux for 6 h, then cooled to 20 °C. The solution was
passed through a syringe filter to remove the catalyst, the resulting
clear yellow solution was evaporated to dryness, and the remaining
solid was recrystallized (i-PrOH). Drying (50 °C/10– mbar) gave 3c
3
(d, J = 7.2 Hz, 3 H, CHCH ), 3.68 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 4.32
3
3
3
(q, J = 7.2 Hz, 2 H, OCH Me), 4.59 (m , 1 H, CHMe), 6.71 (d, J = 7.3 Hz,
2
c
2
4
1
H, NH), 7.49–7.60 (m, 3 H, H ), 7.62–7.71 (m, 1 H, H ), 9.43 (br s, 1
Ar Ar
H, COOH).
3
(1.27 g, 53%) as a colorless solid; mp 167–170 °C.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

G
Synthesis
M. Dobesch et al.
Paper
1
3
1
3
C NMR (CDCl , 101 MHz):  = 13.99 (OCH Me), 17.77 (CHMe), 48.49
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 1.40
3 2
3
2
3
(
CHMe), 52.21 (OMe), 53.02 (OMe), 61.87 (OCH Me), 115.24, 126.11,
(d, J = 7.2 Hz, 3 H, CHMe), 3.71, 3.75, 3.96 (3 s, each 3 H, 3 OMe), 4.35
(q, J = 7.2 Hz, 2 H, OCH Me), 4.64 (m , 1 H, CHMe), 6.48 (d, J = 7.4 Hz,
2
3
3
1
26.78 (C ), 127.75, 130.24, 130.78, 131.57 (CH ), 136.25, 140.42
q
Ar
2
c
(
C ), 157.10 (COOEt), 158.85 (C ), 161.44 and 163.45 (COOMe), 167.57
1 H, NH), 7.52–7.61 (m, 3 H, H ), 7.65–7.72 (m, 1 H, H ).
Ar Ar
q
q
(
NC=O), 175.83 (COOH).
13
C NMR (CDCl , 126 MHz):  = 14.08 (OCH Me), 18.42 (CHMe), 48.48
3
2
+
HRMS (ESI): m/z [2 M + K] calcd: 933.19625; found: 933.19634; m/z
(CHMe), 52.15, 52.53, 52.95 (3 OMe), 61.78 (OCH Me), 115.37, 126.23,
126.85 (C ), 127.69, 130.11, 130.78, 131.61 (CH ), 136.80, 140.55
(C ), 157.08 (COOEt), 158.87 (C ), 161.42, 163.33 (COOMe), 166.90
2
+
+
calcd [M + K] : 486.07970; found: 486.07993; m/z calcd [M + Na] :
70.10577; found: 470.10602.
q
Ar
4
q
q
(NC=O), 173.11 (CHCOOMe).
+
N-{2-[5-(Ethoxycarbonyl)-3,4-bis(methoxycarbonyl)furan-2-
yl]benzoyl}valine (5c)
HRMS (MALDI): m/z [2 M + Na] calcd: 945.25361; found: 945.25182;
+
+
m/z [M + K] calcd: 500.09535; found: 500.09442; m/z [M + Na] cal-
In a thick-walled closed Schlenk tube, a solution of 3c (155 mg, 0.33
mmol) in 1,4-dioxane/water (20 mL/3 mL) was heated at 90 °C for 19
d. After cooling, the precipitate was filtered off and discarded. The fil-
tered solution was concentrated to leave a yellow oil, which contained
the desired product beside unidentified impurities. Isolation and pu-
rification of 5c was not possible, but its presence was indicated by the
expected NMR signals and a molecular ion peak in a mass spectrum.
cd: 484.12142; found: 484.12051.
Anal. Calcd for C22H23NO10 (461.42): C, 57.27; H, 5.02; N, 3.04. Found:
C, 56.95; H, 5.10; N, 2.94.
2,3,4-Trimethyl 5-{2-[(1-Methoxy-1-oxopropan-2-yl)carbam-
oyl]phenyl}furan-2,3,4-tricarboxylate (7b)
A suspension of tetracycle 3b (300 mg, 0.70 mmol) in MeOH (8 mL)
was heated at reflux for 2 h, then the volatiles (MeOH, EtOH) were
evaporated, fresh MeOH was added and heating was continued for 2
h. This procedure was repeated four times. Workup as described for
6b yielded 7b (~65% yield) as a colorless solid, which was character-
+
HRMS (MALDI): m/z [M + H] calcd for C23H26NO10: 476.15512; found:
4
76.15539.
Reactions of Tetracycles 3 with Alcohols
-Ethyl 3,4-Dimethyl 5-{2-[(2-Methoxy-2-oxoethyl)carbam-
1
ized by H NMR only.
2
1
3
H NMR (CDCl , 400 MHz):  = 1.33 (d, J = 7.1 Hz, 3 H, CHMe), 3.64,
3
oyl]phenyl}furan-2,3,4-tricarboxylate (6a)
3
.68, 3.81, 3.90 (4s, each 3 H, 4 OMe), 4.57 (m , 1 H, CHMe), 6.47 (d,
c
3
The yellow solution of tetracycle 3a (350 mg, 0.84 mmol) in anhyd
J = 7.8 Hz, 1 H, NH), 7.45–7.56 (m, 3 H, H ), 7.62 (m, 1 H, H ).
Ar Ar
CH Cl (5 mL) and anhyd MeOH (3 mL) was stirred at r.t. for 30 min.
2
2
The volatiles were evaporated in vacuo and the residue was subjected
to column chromatography (silica gel, EtOAc/Et O, 1:1). The isolated
product was dried (50 °C/10 mbar) to furnish 6a (271 mg, 72%) as a
colorless solid; mp 113–114 °C.
IR (ATR): 1178 (s), 1227 (s), 1532 (m), 1640 (m), 1719 (s), 3293 cm–1
Trimethyl 5-{2-[(1-Methoxy-3-methyl-1-oxobutan-2-yl)carbam-
oyl]phenyl}furan-2,3,4-tricarboxylate (7c)
2
–3
A solution of tetracycle 3c (156 mg, 0.34 mmol) in anhyd MeOH (30
mL) was stirred at 20 °C for 40 h, then heated at reflux during 56 h.
The solution was cooled and concentrated, fresh MeOH (30 mL) was
added, and heating at reflux was continued for 56 h. After cooling to
r.t., the solvent was removed in vacuo and the residue was dissolved
in hot i-PrOH/cyclohexane (1:1). Petroleum ether (40–65 °C) was
added until the solution became turbid. When the mixture was
stored in a freezer at –30 °C, product 7c (ca. 130 mg) separated as a
colorless solid, together with unidentified components which could
not be removed.
(w).
1
3
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 3.70,
3
2
3
3
.76, 3.96 (3 s, each 3 H, 3 OMe), 4.11 (d, J = 5.0 Hz, 2 H, NHCH ), 4.34
2
3
3
(
(
1
q, J = 7.1 Hz, 2 H, OCH Me), 6.45 (t, J = 4.9 Hz, 1 H, NH), 7.51–7.64
m, 3 H, H ), 7.66–7.72 (m, 1 H, H ).
2
Ar
Ar
3
C NMR (CDCl , 126 MHz):  = 14.07 (OCH CH ), 41.72 (CH COOMe),
3
2
3
2
5
1
1
1
2.14 (OMe), 52.41 (OMe), 52.92 (OMe), 61.75 (OCH Me), 115.32,
2
1
H NMR (CDCl , 500 MHz):  = 0.87–0.94 (m, 6 H, CHMe ), 2.10–2.21
26.13, 126.93 (C ), 127.61, 130.19, 130.75, 131.67 (CH ), 136.42,
3
2
q
Ar
(
m, 1 H, CHMe ), 3.70, 3.74, 3.87, 3.96 (4 s, each 3 H, 4 OMe), 4.59 (dd
J = 4.8, 8.6 Hz, 1 H, NCH), 6.43 (d, J = 8.6 Hz, 1 H, NH), 7.53–7.60 (m,
40.56 (C ), 157.10 (COOEt), 158.73 (C ), 161.46 and 163.35 (COOMe),
2
q
q
3
3
67.62 (s, NC=O), 169.95 (s, CH COOMe).
2
3
H, H ), 7.67–7.72 (m, 1 H, H ).
+
A
r
A
r
HRMS (MALDI): m/z [2 M + Na] calcd: 917.22231; found: 917.22082,
13
+
C NMR (CDCl , 126 MHz):  = 17.83, 18.76 (CHMe ), 31.47 (CHMe ),
3 2 2
m/z [M + Na] calcd: 470.10577; found: 470.10490.
5
1
2.16, 52.19, 52.47, 53.02 (OMe), 57.55 (s, NCH), 115.45, 126.39,
26.82 (C ), 127.69, 130.13, 130.81, 131.65 (CH ), 136.90, 140.35
Anal. Calcd for C21H21NO10 (447.39): C, 56.38; H, 4.73; N, 3.13. Found:
q
Ar
56.26; H, 4.78; N, 3.21.
(
C ), 157.50 (COOMe), 159.02 (C ), 161.39, 163.22 (COOMe), 167.39
q
q
(
NC=O), 172.12 (CHCOOMe).
2
-Ethyl 3,4-Dimethyl 5-{2-[(1-Methoxy-1-oxopropan-2-yl)carba-
MS (MALDI): [M] calcd for C23H25NO10 (475.45); m/z = 514 [M + K]+,
4
moyl]phenyl}furan-2,3,4-tricarboxylate (6b)
+
+
98 [M + Na] , 476 [M + H] .
A solution of tetracycle 3b (300 mg, 0.70 mmol, exo-Me/endo-Me 2:1)
in MeOH (8 mL) was stirred at 20 °C for 30 min. The solvent was
evaporated at 35 °C in vacuo and the resulting foam was treated with
PE/i-PrOH. Crystals of endo-3b (115 mg, 38%) were obtained. The
mother liquor was concentrated and the residue was purified by col-
umn chromatography (acetone) to obtain pure 6b (155 mg, 48% based
on 3b) as a pale yellow solid; mp 134–136 °C.
2
-Ethyl 3,4-Dimethyl 5-{2-[(1-Ethoxy-1-oxopropan-2-yl)carbam-
oyl]phenyl}furan-2,3,4-tricarboxylate (6d)
A suspension of tetracycle 3b (215 mg, 0.50 mmol) in anhyd EtOH (8
mL) was heated at reflux during 6 h. The clear solution was cooled, the
solvent was evaporated in vacuo, and the residue was subjected to
column chromatography (silica gel, CH Cl /Et O, 8:2). The product
IR (KBr): 1226 (s), 1636 (m), 1729 (s), 1752 (s), 3287 (m), 3427 cm–1
2
2
2
(br, s).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

H
Synthesis
M. Dobesch et al.
Paper
fraction furnished a yellow oil, which was triturated with Et O (10
2-Ethyl 3,4-Dimethyl 5-{2-[(2-Isopropoxy-2-oxoethyl)carbam-
2
mL) in an ultrasonic bath to give 6d (181 mg, 76%) as a colorless solid;
oyl]phenyl}furan-2,3,4-tricarboxylate (6g)
mp 144–145 °C.
Prepared from tetracycle 3a (250 mg, 0.60 mmol) in anhyd i-PrOH (8
mL) at reflux for 8 h. The reaction solution was brought to r.t., the sol-
vent was evaporated in vacuo, and the residue was recrystallized (i-
PrOH/cyclohexane, crystallization was completed at 7 °C during 20 h)
to give 6g (197 mg, 69%) as a colorless solid; mp 128–129 °C.
IR (KBr): 1177 (s), 1230 (s), 1666 (s), 1729 (s), 1760 (m), 3345 cm–1
(m).
IR (ATR): 1141 (m), 1170 (m), 1222 (s), 1321 (m), 1532 (m), 1634 (m),
–1
1723 (s), 1746 (m), 3271 cm (br, w).
1
3
H NMR (CDCl , 400 MHz):  = 1.28 (t, J = 7.1 Hz, 3 H, OCH Me), 1.34
3
2
3
3
(t, J = 7.1 Hz, 3 H, OCH Me), 1.40 (d, J = 7.1 Hz, 3 H, CHMe), 3.71 (s, 3
2
3
H, OMe), 3.96 (s, 3 H, OMe), 4.20 (q, J = 7.1 Hz, 2 H, OCH Me), 4.34 (q,
2
3
3
J = 7.1 Hz, 2 H, OCH Me), 4.61 (m , 1 H, CHMe), 6.51 (d, J = 7.3 Hz, 1
2
c
H, NH), 7.51–7.62 (m, 3 H, H ), 7.65–7.72 (m, 1 H, H ).
1
3
Ar
Ar
H NMR (CDCl , 400 MHz):  = 1.27 (d, J = 6.3 Hz, 6 H, CHMe ), 1.34 (t,
3
2
13
3
C NMR (CDCl , 126 MHz):  = 14.08 (OCH Me), 18.46 (CHMe), 48.56
J = 7.2 Hz, 3 H, OCH
2
Me), 3.71 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.07
), 4.34 (q, J = 7.2 Hz, 2 H, OCH
), 6.44 (t, J = 4.7 Hz, 1 H, NH), 7.52–7.64 (m, 3
3
2
3
3
(
CHMe), 52.14 and 52.93 (OMe), 61.60 (OCH Me), 61.75 (OCH Me),
(d, J = 5.0 Hz, 2 H, NCH
2
2
Me), 5.08 (m
c
,
2
2
3
3
1
1
15.33, 126.26, 126.89 (s, C ), 127.64, 130.07, 130.76, 131.61 (CH ),
J = 6.3 Hz, 1 H, CHMe
2
q
Ar
36.86, 140.52 (C ), 157.09 (COOEt), 158.91 (C ), 161.41 and 163.34
H, HAr), 7.66–7.73 (m, 1 H, HAr).
q
q
(
COOMe), 166.87 (NC=O), 172.70 (CHCOOEt).
13
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 21.70 (CHMe ), 42.05
3
2
2
+
HRMS (MALDI): m/z [2 M + Na] calcd: 973.28491; found: 973.28377;
m/z [M + K] calcd: 514.11100; found: 514.11059; m/z [M + Na] cal-
cd: 498.13707; found: 498.13665; m/z [M + H] calcd: 476.15512;
(NCH
2
), 52.11 and 52.89 (OCH
3
), 61.71 (OCH
2
Me), 69.46 (CHMe ),
2
+
+
115.27, 126.15, 126.98 (C
136.52, 140.52 (C ), 157.11 (COOEt), 158.78 (C
q
), 127.54, 130.13, 130.72, 131.67 (CHAr),
q
+
), 161.45, 163.38
q
found: 476.15480.
(COOMe), 167.55 (NC=O), 169.09 (COOC H ).
3 7
+
Anal. Calcd for C23H25NO10 (475.45): C, 58.10; H, 5.30; N, 2.95. Found:
C, 58.34; H, 5.25; N, 2.92.
HRMS (MALDI): m/z [2 M + Na] calcd: 973.28491; found: 973.28394;
+
+
m/z [M + K] calcd: 514.11100; found: 514.11094; m/z [M + Na] cal-
cd: 498.13707; found: 498.13694; m/z [M + H] calcd: 476.15512;
+
found: 476.15505.
2-Ethyl 3,4-Dimethyl 5-{2-[(1-Ethoxy-3-methyl-1-oxobutan-2-
yl)carbamoyl]phenyl}furan-2,3,4-tricarboxylate (6e)
Anal. Calcd for C23H25NO10 (475.45): C, 58.10; H, 5.30; N, 2.95. Found:
C, 57.97; H, 5.35; N, 3.12.
In a thick-walled Schlenk tube, a solution of 3c (0.30 mmol) in anhyd
EtOH was heated at 70 °C during 232 h. After cooling, the solid precip-
itate was filtered off and the filtrate was concentrated to afford a
brown oil, which contained 6c beside a considerable amount of un-
identified material. Isolation and purification of 6e was not possible,
but its presence was indicated by the expected NMR and MS data.
2-Ethyl 3,4-Dimethyl 5-(2-{[2-(Benzyloxy)-2-oxoethyl]carbam-
oyl}phenyl)furan-2,3,4-tricarboxylate (6h)
Tetracycle 3a (150 mg, 0.36 mmol) was suspended in benzyl alcohol
(
4 mL) and heated at 65 °C for 6 h. Evaporation of excess alcohol at
+
–3
HRMS (MALDI): m/z [M + K] calcd: 542.14230; found: 542.14296;
130 °C/10 mbar followed by column chromatography (Et
2
O) gave 6h
+
m/z [M + Na] calcd: 526.16837; found: 526.16902.
(129 mg, 68%) as a colorless solid; DSC: T
g
= 32 °C.
IR (ATR): 1175 (s), 1231 (s), 1663 (m), 1720 cm–1 (s).
2
-Ethyl 3,4-Dimethyl 5-{2-[(1-Oxo-1-propoxypropan-2-yl)carba-
1
3
H NMR (CDCl , 400 MHz):  = 1.32 (t, J = 7.1 Hz, 3 H, OCH Me), 3.69
3
2
moyl]phenyl}furan-2,3,4-tricarboxylate (6f)
3
(s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.14 (d, J = 5.1 Hz, 2 H, NCH ), 4.32
2
3
Prepared from tetracycle 3b (200 mg, 0.47 mmol) in anhyd PrOH (8
mL) at 90 °C for 6 h as described for 6a. Column chromatography
(q, J = 7.1 Hz, 2 H, OCH Me), 5.19 (s, 2 H, PhCH ), 6.50 (m , 1 H, NH),
7.30–7.40 (m, 5 H, H ), 7.48–7.73 (m, 4 H, H ).
2
2
c
Ar
Ar
(
Et O) gave 6f (182 mg, 80%) as a colorless solid; mp 99–101 °C.
13
2
C NMR (CDCl , 126 MHz):  = 14.04 (OCH Me), 41.81 (NCH ), 52.11
3
2
2
IR (KBr): 1220 (s), 1638 (s), 1725 (s), 1752 (s), 3301 (m), 3425 cm–1
(OMe), 52.91 (OMe), 61.71 (OCH Me), 67.22 (CH Ph), 115.24, 126.12,
2
2
(br, m).
126.93 (C ), 127.54, 128.35, 128.49, 128.59, 130.15, 130.71, 131.66
q
1
3
(CH ), 135.10, 136.37, 140.50 (C ), 157.08 (COOEt), 158.74 (C ),
161.44 and 163.36 (COOMe), 167.64 (NC=O), 169.44 (COOCH Ph).
2
H NMR (CDCl , 400 MHz):  = 0.94 (t, J = 7.4 Hz, 3 H, OCH CH Me),
A
r
q
q
3
2
2
3
3
1
1
4
.33 (t, J = 7.2 Hz, 3 H, OCH Me), 1.40 (d, J = 7.1 Hz, 3 H, CHMe),
.61–1.72 (m, 2 H, CH Me), 3.70 (s, 3 H, OMe), 3.95 (s, 3 H, OMe),
.05–4.16 (m, 2 H, OCH CH ), 4.34 (q, J = 7.1 Hz, 2 H, OCH Me), 4.63
2
Na]+ calcd: 1069.28491; found:
2
HRMS (MALDI): m/z [2
M
+
3
+
2
2
2
1069.28222; m/z [M + K] calcd: 562.11100; found: 562.11078; m/z
3
+
+
(m , 1 H, CHMe), 6.53 (d, J = 7.2 Hz, 1 H, NH), 7.51–7.62 (m, 3 H, H ),
[M + Na] calcd: 546.13707; found: 546.13669; m/z [M + H] calcd:
c
Ar
7.64–7.72 (m, 1 H, HAr).
524.15512; found 524.15475.
1
3
C NMR (CDCl , 126 MHz):  = 10.15 (CH CH Me), 13.98 (OCH Me),
Anal. Calcd for C27H25NO10 (523.49): C, 61.95; H, 4.81; N, 2.68. Found:
C, 61.94; H, 4.75; N, 2.62.
3
2
2
2
1
8.35 (CHMe), 21.78 (OCH CH ), 48.47 (CHMe), 52.04 and 52.84
2 2
(
OMe), 61.65 (OCH Me), 67.02 (OCH CH ), 115.20, 126.18, 126.80
2
2
2
(
1
C ), 127.54, 129.98, 130.67, 131.51 (CH ), 136.73, 140.39 (C ),
q
A
r
q
2-Ethyl 3,4-Dimethyl 5-(2-{[1-(Benzyloxy)-1-oxopropan-2-yl]car-
bamoyl}phenyl)furan-2,3,4-tricarboxylate (6i)
56.98 (COOEt), 158.85 (C ), 161.30 and 163.25 (COOMe), 166.81
q
(NC=O), 172.68 (COOC H ).
3 7
Prepared as described above for 6h from tetracycle 3b (125 mg, 0.29
mmol) in benzyl alcohol (3 mL) at 100 °C for 12 h to give 6i (97 mg,
HRMS (MALDI): m/z [2
1
M +
Na]+ calcd: 1001.31621; found:
+
001.31658; m/z [M + K] calcd: 528.12665; found: 528.12646; m/z
6
2%) as an amorphous yellow solid; DSC: T = 36 °C.
g
+
+
[
4
M + Na] calcd: 512.15272; found: 512.15252; m/z [M + H] calcd:
90.17077; found: 490.17076.
IR (ATR): 1160 (s), 1229 (s), 1663 (m), 1722 (s), 3366 cm–1 (br, w).
Anal. Calcd for C24H27NO10 (489.48): C, 58.89; H, 5.56; N, 2.86. Found:
C, 59.10; H, 5.65; N, 2.77.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

I
Synthesis
M. Dobesch et al.
Paper
1
3
H NMR (CDCl , 400 MHz):  = 1.33 (t, J = 7.1 Hz, 3 H, OCH Me), 1.41
(CH ), 131.36 (H C=CHCH ), 131.67 (CH ), 136.34 (C ), 140.47 (C ),
3
2
Ar
2
2
Ar
q
q
3
(d, J = 7.1 Hz, 3 H, CHMe), 3.69 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.33
157.08 (COOEt), 158.76 (C ), 161.44 and 163.38 (COOMe), 167.62
q
3
(q, J = 7.1 Hz, 2 H, OCH Me), 4.69 (m , 1 H, CHMe), 5.14–5.23 (AB sys-
(NC=O), 169.25 (NCH C=O).
2
c
2
3
tem, 2 H, OCH Ph), 6.51 (d, J = 7.3 Hz, 1 H, NH), 7.29–7.72 (m, 9 H,
H ).
+
2
HRMS (MALDI): m/z [M + K] calcd: 512.09535; found: 512.09520;
Ar
m/z [M + Na] calcd: 496.12142; found: 496.12120; m/z [M + H] cal-
+
+
13
C NMR (CDCl , 126 MHz):  = 14.09 (OCH Me), 18.42 (CHMe), 48.56
cd: 474.13947; found: 474.13931.
3
2
(
CHMe), 52.18 (OMe), 52.99 (OMe), 61.78 (OCH Me), 67.25 (OCH Ph),
2
2
Anal. Calcd for C23H23NO10 (473.43): C, 58.35; H, 4.90; N, 2.96. Found:
C, 58.29; H, 5.14; N, 2.82.
1
1
1
15.29, 126.24, 126.85 (C ), 127.62, 128.16, 128.46, 128.62, 130.12,
q
30.77, 131.65 (CH ), 135.25, 136.75, 140.49 (C ), 157.08 (COOEt),
Ar
q
58.90 (C ), 161.42 and 163.39 (COOMe), 166.94 (NC=O), 172.58 (CH-
q
Reaction of Tetracycle 3b with Thiolates
COOCH2).
HRMS (MALDI): m/z [2
M +
Na]+ calcd: 1097.31621; found:
2
-Ethyl 3,4-Dimethyl 5-(2-{[1-Oxo-1-(phenylthio)propan-2-yl]car-
+
1
097.31224; m/z [M + K] calcd: 576.12665; found: 576.12610; m/z
bamoyl}phenyl)furan-2,3,4-tricarboxylate (8a)
+
[
M + Na] calcd: 560.15272; found: 560.15220.
To a solution of tetracycle 3b (200 mg, 0.46 mmol) in anhyd CH Cl (5
mL) was added benzenethiol (57 L, 0.56 mmol) and dry NEt (97 L,
2
2
Anal. Calcd for C28H27NO10 (537.52): C, 62.57; H, 5.06; N, 2.61. Found:
C, 62.41; H, 5.15; N, 2.49.
3
0.70 mmol). The deep-yellow solution was stirred for 30 min, then
the volatiles were evaporated. The resulting brown foam was purified
2-Ethyl 3,4-Dimethyl 5-(2-{[2-(Hex-5-enyloxy)-2-oxoethyl]carba-
by column chromatography (silica gel, Et O) to afford 8a (174 mg,
2
moyl}phenyl)furan-2,3,4-tricarboxylate (6j)
69%) as an amorphous colorless solid; DSC: T = 36 °C.
g
Tetracycle 3a (322 mg, 0.78 mmol) was suspended in anhyd hex-5-
IR (KBr): 1179 (m), 1237 (m), 1656 (m), 1727 (s), 3427 cm–1 (vs).
en-1-ol (6 mL) and heated at 95 °C for 6 h. Evaporation of excess alco-
1
3
H NMR (CDCl , 400 MHz):  = 1.32 (t, J = 7.1 Hz, 3 H, OCH Me), 1.49
–3
3
2
hol at 100 °C/10 mbar followed by column chromatography (Et O)
2
3
(d, J = 7.1 Hz, 3 H, CHMe), 3.71 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 4.31
furnished 6j (284 mg, 71%) as a colorless viscous oil.
3
3
(q, J = 7.1 Hz, 2 H, OCH Me), 4.90 (m , 1 H, CHMe), 6.46 (d, J = 7.9 Hz,
2
c
IR (NaCl): 1239 (br, s), 1309 (s), 1411 (s), 1450 (s), 1534 (s), 1666 (s),
1
H, NH), 7.38–7.44 (m, 5 H, H ), 7.54–7.62 (m, 3 H, H ), 7.72–7.77
Ar Ar
–1
1
747 (s), 3379 cm (br, m).
(m, 1 H, HAr).
1
3
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 1.40–
13
3
2
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 18.79 (CHMe), 52.24
3 2
1
.50 (m, 2 H, OCH CH CH ), 1.57–1.74 (m, 2 H, OCH CH CH ), 2.00–
2 2 2 2 2 2
and 52.97 (OMe), 55.33 (CHMe), 61.83 (OCH Me), 115.38, 126.14,
2
2
.16 (m, 2 H, H C=CHCH ), 3.70 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.10
2
2
126.60, 126.89 (C ), 127.60, 129.24, 129.60, 130.31, 130.86, 131.73,
q
3
3
(d, J = 5.0 Hz, 2 H, NCH ), 4.16 (t, J = 6.7 Hz, 2 H, OCH CH CH ), 4.34
2
2
2
2
134.68 (CH ), 136.55, 140.57 (C ), 157.06 (COOEt), 158.87 (C ),
Ar
q
q
3
(q, J = 7.1 Hz, 2 H, OCH Me), 4.90–5.07 (m, 2 H, H C=CHCH ), 5.70–
2
2
2
161.51 (COOMe), 163.34 (COOMe), 167.15 (NC=O), 198.61 (SC=O).
5
.86 (m, 1 H, H C=CHCH ), 6.46 (br t, 1 H, NH), 7.50–7.73 (m, 4 H, H ).
2
2
A
r
+
HRMS (MALDI): m/z [M + K] calcd: 578.08816; found: 578.08769;
13
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 25.02 (O(CH ) CH ),
+
+
3
2
2
2
2
m/z [M + Na] calcd: 562.11422; found: 562.11378; m/z [M + H] cal-
2
7.87 (OCH CH ), 33.16 (H C=CHCH ), 41.80 (NCH ), 52.14, 52.93
2 2 2 2 2
cd: 540.13228; found: 540.13189.
(
OMe), 61.73 (OCH Me), 65.51 (OCH CH ), 114.95 (H C=CHCH ),
2 2 2 2 2
Anal. Calcd for C27H25NO S (539.56): C, 60.10; H, 4.67; N, 2.60; S, 5.94.
9
1
15.24 (C ), 126.14 (C ), 126.96 (C ), 127.52, 130.16, 130.73, 131.70
q q q
Found: C, 59.90; H, 4.80; N, 2.44; S, 5.70.
(
CH ), 136.43 (C ), 138.12 (H C=CHCH ), 140.50 (C ), 157.10 (COOEt),
Ar q 2 2 q
1
58.79 (C ), 161.45 and 163.39 and 167.60 (NC=O), 169.64 (NCH CO).
q
2
2
-Ethyl 3,4-Dimethyl 5-(2-{[1-(Cyclohexylthio)-1-oxopropan-2-
HRMS (MALDI): m/z [2
M
+
Na]+ calcd: 1053.34751; found:
yl]carbamoyl}phenyl)furan-2,3,4-tricarboxylate (8b)
+
1053.34394; m/z [M + Na] calcd: 538.16837; found: 538.16789.
A solution of cyclohexanethiol (112 L, 0.92 mmol) and DBU (112 L,
0.75 mmol) in anhyd CH Cl (5 mL) was added dropwise to a solution
of tetracycle 3b (320 mg, 0.75 mmol) in anhyd CH Cl (5 mL). The
Anal. Calcd for C26H29NO10 (515.52): C, 60.58; H, 5.67; N, 2.72. Found:
C, 60.32; H, 5.69; N, 2.79.
2
2
2
2
deep-red solution was stirred for 30 min, then concentrated. Column
chromatography (silica gel, cyclohexane/EtOAc, 2:8) furnished 8b
2-Ethyl 3,4-Dimethyl 5-(2-{[2-(Allyloxy)-2-oxoethyl]carbam-
oyl}phenyl)furan-2,3,4-tricarboxylate (6k)
(269 mg, 66%) as an amorphous yellow solid; DSC: T = 32 °C.
g
Prepared as described for 6j from tetracycle 3a (200 mg, 0.48 mmol)
and allyl alcohol (4 mL) at 85 °C for 6 h to give 6k (153 mg, 67%) as a
colorless oil.
IR (NaCl): 1186 (s), 1236 (s), 1531 (m), 1669 (s), 1750 (s), 3384 cm–1
IR (KBr): 1178 (m), 1234 (m), 1673 (m), 1729 (s), 3424 cm–1 (br, m).
1
H NMR (CDCl , 400 MHz):  = 1.17–1.50 (m, 11 H, OCH Me, CHMe, 5
3
2
CHc-hex), 1.54–1.77 (m, 3 H, CHc-hex), 1.84–1.98 (m, 2 H, CHc-hex), 3.44–
3
3
7
.55 (m, 1 H, SCH), 3.71 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.34 (q, J =
(br, m).
3
.1 Hz, 2 H, OCH Me), 4.73 (m , 1 H, CHMe), 6.46 (d, J = 7.9 Hz, 1 H,
2
c
1
3
H NMR (CDCl , 500 MHz):  = 1.33 (t, J = 7.1 Hz, 3 H, OCH Me), 3.70
NH), 7.52–7.62 (m, 3 H, HAr), 7.68–7.75 (m, 1 H, HAr).
3
2
3
(s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.13 (d, J = 5.1 Hz, 2 H, NCH ), 4.33
13
2
C NMR (CDCl , 126 MHz):  = 14.10 (OCH Me), 19.15 (CHMe), 25.46
3 2
3
3
(q, J = 7.1 Hz, 2 H, OCH Me), 4.65 (d, J = 5.8 Hz, 2 H, H C=CHCH ),
2
2
2
(C-4c-hex), 25.93 (C-3c-hex), 32.88 (C-2c-hex), 42.56 (SCH), 52.20 and
5
.20–5.37 (m, 2 H, H C=CHCH ), 5.84–5.96 (m, 1 H, H C=CHCH ), 6.48
2
2
2
2
52.96 (OMe), 55.43 (CHMe), 61.80 (OCH Me), 115.30, 126.19, 126.83
2
(
br t, 1 H, NH), 7.49–7.63 (m, 3 H, H ), 7.66–7.71 (m, 1 H, H ).
A
r
A
r
(C ), 127.62, 130.16, 130.81, 131.68 (CH ), 136.70, 140.49 (C ),
q
Ar
q
13
C NMR (CDCl , 126 MHz):  = 14.06 (OCH Me), 41.75 (NCH ), 52.15
157.06 (COOEt), 158.91 (C ), 161.46 and 163.34 (COOMe), 166.87
q
3
2
2
and 52.93 (OMe), 61.73 (OCH Me), 66.08 (H C=CHCH ), 115.21 (C ),
(NC=O), 200.03 (SC=O).
2
2
2
q
1
19.01 (H C=CHCH ), 126.10, 126.92 (C ), 127.53, 130.18, 130.73
2
2
q
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

J
Synthesis
M. Dobesch et al.
Paper
Na]+ calcd: 1113.33313; found:
1
H NMR (CD Cl , 500 MHz):  = 1.29 (t, J = 7.1 Hz, 3 H, OCH Me), 3.62
2 2 2
3
HRMS (MALDI): m/z [2
M
+
+
3
1
113.33489; m/z [M + K] calcd: 584.13586; found: 584.13511; m/z
(s, 3 H, OMe), 3.90 (s, 3 H, OMe), 3.99 (d, J = 5.2 Hz, 2 H, CH C=O),
4.27 (q, J = 7.1 Hz, 2 H, OCH Me), 4.41 (d, J = 5.9 Hz, 2 H, CH Ph), 6.53
2 2
2
+
3
3
[
M + Na] calcd: 568.16117; found 568.16190.
(
br t, 1 H, PhCH NH), 6.88 (br t, 1 H, NHCH C=O), 7.19–7.34 (m, 5 H,
Anal. Calcd for C27H31NO S (545.60): C, 59.44; H, 5.73; N, 2.57; S, 5.88.
Found: C, 59.30; H, 5.78; N, 2.71; S, 5.90.
2
2
9
H ), 7.52–7.61 (m, 3 H, H ), 7.64–7.71 (m, 1 H, H ).
1
Ar
Ar
Ar
3
C NMR (CD Cl , 126 MHz):  = 14.40 (OCH Me), 43.81 (PhCH ), 44.22
2
2
2
2
(
1
NHCH C=O), 52.60 (OMe), 53.43 (OMe), 62.39 (OCH Me), 115.41 (C ),
Reactions of Tetracycles 3 with NH-Nucleophiles; General Proce-
dure
2
2
q
26.53 (C ), 127.84, 127.90, 127.96, 129.11, 130.91, 131.35, 132.26
q
(CH ), 136.84, 138.86, 140.87 (C ), 157.63 (COOEt), 159.83 (C ),
A
r
q
q
Liquid amines (benzylamine, cyclohexylamine, allylamine, and tert-
butylamine) were dried over powdered KOH and distilled. A solution
of a tetracycle 3 (~0.2–0.7 mmol) in anhyd CH Cl (4–5 mL) was treat-
1
62.01 (COOMe), 163.76 (COOMe), 168.36 (NCH NHC=O), 168.90
2
(PhCH NHC=O).
2
2
2
+
+
+
ed with a moderate excess of a primary or secondary amine (for reac-
tion conditions see individual compounds). The resulting yellow clear
MS (MALDI): m/z = 561 [M + K] , 545 [M + Na] , 523 [M + H] .
Anal. Calcd for C27H26N O (522.51): C, 62.07; H, 5.02; N, 5.36. Found:
C, 62.14; H, 5.02; N, 5.28.
2
9
solution was diluted with CH Cl (10 mL) and transferred to a separa-
2
2
tory funnel. After extraction with 2 M aq HCl (3 × 10 mL) and water (2
10 mL), the organic phase was separated, dried (Na SO ), filtered,
×
2
4
2
-Ethyl 3,4-Dimethyl 5-(2-{[1-(Benzylamino)-1-oxopropan-2-
and the solvent was removed in vacuo. The crude product was recrys-
yl]carbamoyl}phenyl)furan-2,3,4-tricarboxylate (9c)
–3
tallized (EtOAc/PE) and dried (50 °C/10 mbar).
Prepared from 3b (140 mg, 0.33 mmol) and benzylamine (47 L, 0.43
mmol) at 20 °C for 5 min to give 9c (159 mg, 91%) as a colorless solid;
mp 162–163 °C.
2
-Ethyl 3,4-Dimethyl 5-{2-[(2-Amino-2-oxoethyl)carbamoyl]phe-
nyl}furan-2,3,4-tricarboxylate (9a)
a) From tetracycle 3a: A solution of 3a (96 mg, 0.23 mmol) in anhyd
CH Cl (3 mL) was combined with 0.5 M ammonia in 1,4-dioxane
IR (ATR): 1234 (s), 1555 (s), 1633 (m), 1714 (m), 1730 (m), 1748 (m),
3
(
–1
205 (br, w), 3283 cm (br, w).
2
2
1
3
H NMR (CD Cl , 400 MHz):  = 1.31 (t, J = 7.1 Hz, 3 H, OCH Me), 1.38
solution. After stirring at r.t. for 5 min, more CH Cl (10 mL) was add-
2
2
2
2
2
3
(d, J = 6.9 Hz, 3 H, CHMe), 3.65 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 4.24–
ed and the solution was transferred to a separatory funnel. After ex-
traction with water (10 mL) the organic layer was separated, dried
4
.57 (m, 5 H, CHMe, CH NH, OCH Me), 6.52 (br t, 1 H, CH NH), 6.69 (d,
2
2
2
3
J = 7.4 Hz, 1 H, CHNH), 7.19–7.38 (m, 5 H, H ), 7.54–7.70 (m, 4 H,
(
Na SO ), and filtered and the volatiles were evaporated in vacuo. The
Ar
2
4
–3
H ).
1
residue was dried (50 °C/10 mbar) to give 9a (92 mg, 92%) as a col-
Ar
3
orless solid.
C NMR (CDCl , 101 MHz):  = 14.06 (OCH Me), 18.11 (CHMe), 43.41
3 2
(
1
1
CH NH), 49.28 (CHMe), 52.19 (OMe), 52.98 (OMe), 61.82 (OCH Me),
15.04, 126.18, 126.96 (C ), 127.38, 127.40, 127.53, 128.62, 130.22,
q
(
b) From N-tert-butyl carboxamide 9f: A solution of 9f (123 mg, 0.25
2
2
mmol) in TFA (3 mL) was kept at 65 °C for 10 h. The volatiles were
evaporated and the residue was purified by column chromatography
30.76, 131.69 (CH ), 136.53, 137.94, 140.38 (C ), 157.07 (COOEt),
Ar
q
(
acetone). The desired product was isolated and dried (50 °C/10–3
159.11 (C ), 161.42 and 163.34 (COOMe), 167.51 (CHNHC=O), 171.57
q
(CH NHC=O).
mbar) to give 9a (82 mg, 75%) as a colorless solid; mp 184–185 °C.
2
+
+
MS (MALDI): m/z = 575 [M + K] , 559 [M + Na] .
IR (ATR): 1170 (s), 1227 (m), 1648 (s), 1684 (m), 1701 (m), 1728 (s),
3
–1
372 (w), 3439 cm (w).
Anal. Calcd for C28H28N O (536.54): C, 62.68; H, 5.26; N, 5.22. Found:
2
9
1
3
C, 62.51; H, 5.20; N, 5.27.
H NMR (DMSO-d , 400 MHz):  = 1.26 (t, J = 7.1 Hz, 3 H, OCH Me),
6
2
3
3
4
.61 (s, 3 H, OMe), 3.68 (d, J = 5.8 Hz, 2 H, CH NH), 3.86 (s, 3 H, OMe),
.29 (q, J = 7.1 Hz, 2 H, OCH Me), 7.09 (s, 1 H, CONH), 7.25 (s, 1 H,
2
3
2-Ethyl 3,4-Dimethyl 5-(2-{[1-(Benzylamino)-3-methyl-1-oxobu-
tan-2-yl]carbamoyl}phenyl)furan-2,3,4-tricarboxylate (9d)
2
3
CONH), 7.60–7.70 (m, 3 H, H ), 7.83–7.88 (m, 1 H, H ), 8.74 (t, J = 5.8
Ar
Ar
Hz, 1 H, CH NH).
2
Prepared from tetracycle 3c (100 mg, 0.22 mmol) and benzylamine
(60 L, 0.55 mmol) at reflux for 16 h. The crude product was triturat-
13
C NMR (DMSO-d , 126 MHz):  = 13.93 (OCH Me), 42.37 (CH NH),
6
2
2
5
2.08 and 52.87 (OMe), 61.62 (COOCH Me), 113.93, 126.06, 126.95
ed with Et O in an ultrasonic bath for 5 min. Filtration and drying
(80 °C/10 mbar) gave 9d (63 mg, 51%) as a colorless solid; mp 190–
191 °C.
2
3
2
–
(C ), 128.03, 130.08, 130.64, 131.42 (CH ), 136.40 (C ), 139.05 (C ),
q
Ar
q
q
156.54 (COOEt), 159.92 (C ), 160.85 and 162.71 (COOMe), 166.96
q
(
CONH), 170.60 (CONH2).
IR (KBr): 1231 (m), 1635 (s), 1731 (s), 3273 cm–1 (m).
+
HRMS (MALDI): m/z [2 M + Na] calcd: 887.22298; found: 887.22244;
m/z [M + K] calcd: 471.08004; found: 471.07992; m/z [M + Na] cal-
cd: 455.10610; found: 455.10597.
1
3
H NMR (500 MHz, CD Cl ):  = 0.88–0.98 (m, 6 H, CHMe ), 1.31 (t, J =
2
2
2
+
+
7
.1 Hz, 3 H, OCH Me), 2.08–2.19 (m, 1 H, CHMe ), 3.63 (s, 3 H, OMe),
2
2
3
.92 (s, 3 H, OMe), 4.23–4.33 (m, 3 H, OCH Me, NHCH), 4.33–4.50 (AB
2
2
3
A
B
Anal. Calcd for C20H20N O (432.39): C, 55.56; H, 4.66; N, 6.48. Found:
C, 55.60; H, 4.64; N, 6.40.
part of ABX spin system, J = 14.9 Hz, J = 6.1 Hz, 2 H, NCH H ), 6.31
(br t, 1 H, NHCH
2
9
3
), 6.68 (d, J = 8.2 Hz, 1 H, NHCH), 7.20–7.36 (m, 5 H,
2
H ), 7.53–7.62 (m, 3 H, H ), 7.64–7.72 (m, 1 H, H ).
Ar
Ar
Ar
13
2-Ethyl 3,4-Dimethyl 5-(2-{[2-(Benzylamino)-2-oxoethyl]carbam-
C NMR (126 MHz, CD Cl ):  = 14.43 (OCH Me), 18.44 and 19.62
2 2 2
oyl}phenyl)furan-2,3,4-tricarboxylate (9b)
(CHMe ), 31.87 (CHMe ), 43.91 (NCH ), 52.60 and 53.40 (OMe), 59.52
2 2 2
(
1
1
NCH), 62.35 (OCH Me), 115.56, 126.59 (C ), 127.87, 127.91, 128.10,
29.14, 130.79, 131.32, 132.25 (CH ), 137.40, 138.90, 140.93 (C ),
Ar q
Prepared from 3a (150 mg, 0.36 mmol) and benzylamine (51 L, 0.47
mmol) at 20 °C for 5 min to give 9b (157 mg, 83%) as a colorless solid;
mp 116–117 °C.
IR (ATR): 1177 (s), 1228 (s), 1543 (m), 1638 (m), 1726 (s), 3226 cm–1
2
q
57.59 (COOEt), 160.02 (C ), 161.93 and 163.76 (COOMe), 167.92
q
(CqC=O), 171.00 (CHC=O).
(br, w).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

K
Synthesis
M. Dobesch et al.
Paper
+
+
MS (CI): m/z = 565 [M + H] , 458 [M – NHCH Ph] , 430 [M – CON-
2-Ethyl 3,4-Dimethyl 5-(2-{[1-(Cyclohexylamino)-1-oxopropan-2-
yl]carbamoyl}phenyl)furan-2,3,4-tricarboxylate (9g)
2
+
+
HCH Ph] , 357 [M – CONHCH Ph – COOEt] , 341 [M + H – NHCH Ph –
2
2
2
+
2
COOMe] .
Prepared from tetracycle 3b (150 mg, 0.35 mmol) and cyclohexyl-
amine (52 L, 0.46 mmol) at r.t. for 5 min. The product obtained after
Anal. Calcd for C30H32N O (564.59): C, 63.82; H, 5.71; N, 4.96. Found:
2
9
C, 63.65; H, 5.66; N, 5.02.
workup was recrystallized (i-Pr O) to give 9g (126 mg, 68%) as a col-
2
orless solid; mp 179–181 °C.
2
-Ethyl 3,4-Dimethyl 5-(2-{[2-(Allylamino)-2-oxoethyl]carbam-
IR (ATR): 1235 (s), 1555 (m), 1632 (m), 1724 (m), 3194 (br, w), 3285
cm (br, w).
–1
oyl}phenyl)furan-2,3,4-tricarboxylate (9e)
1
Prepared from tetracycle 3a (178 mg, 0.43 mmol) and allylamine (48
mL, 0.64 mmol) at r.t. for 5 min. After evaporation of the solvent, a
yellow foam resulted, which was redissolved in acetone and subjected
to flash chromatography (silica gel, acetone). The isolated product
H NMR (CDCl , 400 MHz):  = 1.02–1.22 (m, 3 H), 1.25–1.41 (m, 8 H,
3
OCH Me, CHMe, 2 H
3.64–3.77 (m, 4 H, OMe, NCHCH ), 3.96 (s, 3 H, OMe), 4.34 (q, J = 7.1
Hz, 2 H, OCH Me), 4.43 (m , J = 6.9 Hz, 1 H, CHMe), 6.00 (d, J = 8.2 Hz,
1 H, NHCHCH ), 6.70 (d, J = 7.4 Hz, 1 H, NHCHMe), 7.50–7.67 (m, 4 H,
), 1.53–1.77 (m, 3 H), 1.78–1.91 (m, 2 H),
2
c-hex
3
2
3
3
2
c
–3
3
was dried (50 °C/10 mbar) to give 9e (186 mg, 92%) as an amor-
2
phous yellow solid; DSC: T = 44 °C.
H ).
g
Ar
IR (ATR): 1241 (s), 1624 (s), 1690 (m), 1717 (s), 1746 (m), 3290 cm–1
13
C NMR (CDCl , 101 MHz):  = 14.10 (s, OCH Me), 18.47 (CHMe),
3
2
(m).
24.74 (CH ), 25.40 (CH ), 32.82 and 32.85 (NCHCH ), 48.41 (NCHCH ),
2
2
2
2
1
3
49.39 (CHMe), 52.21 and 52.98 (OMe), 61.80 (OCH Me), 115.12,
2
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 3.69
3
2
1
26.24, 126.98 (C ), 127.44, 130.15, 130.77, 131.71 (CHAr), 136.68
(s, 3 H, OMe), 3.85–3.91 (m , 2 H, NHCH CH=), 3.96 (s, 3 H, OMe), 4.01
q
c
2
3
3
(C ), 140.39 (C ), 157.08 (COOEt), 159.10 (C ), 161.42 and 163.37
(d, J = 5.3 Hz, 2 H, NHCH C=O), 4.34 (q, J = 7.1 Hz, 2 H, OCH Me),
q
q
q
2
2
(
COOMe), 167.29 (CH CHNHC=O), 170.67 (CH CHC=O).
3 3
5
.05–5.21 (m, 2 H, =CH ), 5.72–5.87 (m, 1 H, NHCH CH=), 6.30 (br t, 1
2
2
+
+
+
H, NHCH CH=), 6.80 (br t, 1 H, NHCH C=O), 7.52–7.70 (m, 4 H, H ).
MS (CI): m/z = 529 [M + H] , 528 [M] , 430 [M – NH-cyclohexyl] , 359
2
2
Ar
+
13
[M – NHCHR ] .
C NMR (CDCl , 126 MHz):  = 14.06 (OCH Me), 41.83 (NHCH CH=),
2
3
2
2
4
3.87 (NHCH C=O), 52.16 and 52.93 (OMe), 61.81 (OCH Me), 114.96
Anal. Calcd for C27H32N O (528.56): C, 61.36; H, 6.10; N, 5.30. Found:
2
2
2
9
(
Cq), 116.35 (CH2,olefin), 126.09, 127.26 (C ), 127.38, 130.33, 130.74,
C, 61.24; H, 6.05; N, 5.25.
q
1
31.79 (CH ), 133.64 (CH
), 136.19 (C ), 140.39 (C ), 157.12
Ar
olefin q q
(
(
COOEt), 159.21 (C ), 161.53 and 163.34 (COOMe), 168.09 and 168.42
C=Oamide).
q
2-Ethyl 3,4-Dimethyl 5-(2-{[3-Methyl-1-oxo-1-(propylamino)bu-
tan-2-yl]carbamoyl}phenyl)furan-2,3,4-tricarboxylate (9h)
+
HRMS (MALDI): m/z [2 M + Na] calcd: 967.28558; found: 967.28463;
m/z [M + K] calcd: 511.11134; found: 511.11105; m/z [M + Na] cal-
cd: 495.13740; found: 495.13708.
Prepared from 3c (110 mg, 0.24 mmol) and propylamine (30 L, 0.37
mmol) in anhyd EtOAc (25 mL) at 20 °C for 40 h. The crude product
+
+
was triturated with Et O in an ultrasonic bath for 5 min. After filtra-
2
Anal. Calcd for C23H24N O (472.45): C, 58.47; H, 5.12; N, 5.93. Found:
tion, the product was recrystallized (i-PrOH/PE) to give 9h (71 mg,
2
9
C, 58.68; H, 5.16; N, 5.87.
57%) as a colorless solid; mp 183–184 °C.
IR (KBr): 1248 (s), 1639 (s), 1732 (s), 3239 (m), 3334 cm–1 (m).
2
-Ethyl 3,4-Dimethyl 5-(2-{[2-(tert-Butylamino)-2-oxoethyl]car-
1
H NMR (CDCl , 400 MHz):  = 0.85–0.96 (m, 9 H, NCH CH Me,
3
2
2
bamoyl}phenyl)furan-2,3,4-tricarboxylate (9f)
3
CHMe ), 1.33 (t, J = 7.1 Hz, 3 H, OCH Me), 1.42–1.55 (m , 2 H,
2
2
c
Prepared from tetracycle 3a (350 mg, 0.84 mmol) and tert-butyl-
amine (132 mL, 1.26 mmol) at r.t. for 10 min to give 9f (384 mg, 93%)
as a yellow solid; mp 61–62 °C.
IR (ATR): 1177 (m), 1227 (s), 1647 (m), 1724 (s), 3319 cm–1 (br, w).
NCH CH ), 2.05–2.15 (m , 1 H, CHMe ), 3.06–3.18 and 3.20–3.32 (2 m,
2 2 c 2
A
B
3
2 H, NCH H C H ), 3.68 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.22 (dd, J =
2
5
3
7.0 and 8.7 Hz, 1 H, NHCH), 4.33 (q, J = 7.2 Hz, 2 H, OCH Me), 6.07
(m , 1 H, NHCH ), 6.70 (d, J = 8.7 Hz, 1 H, NHCH), 7.52–7.58 (m, 3 H,
2
3
c
2
H ), 7.61–7.70 (m, 1 H, H ).
1
Ar
Ar
H NMR (CDCl , 400 MHz):  = 1.29–1.39 (m, 12 H, OCH Me, NHCMe ),
3
2
3
13
3
C NMR (CDCl , 126 MHz):  = 11.31 (NCH CH Me), 14.08 (OCH Me),
3 2 2 2
3
4
.69 (s, 3 H, OMe), 3.89 (d, J = 4.8 Hz, 2 H, CH NH), 3.95 (s, 3 H, OMe),
2
3
18.24 and 19.16 (CHMe ), 22.70 (NCH CH Me), 31.25 (CHMe ), 41.20
.34 (q, J = 7.1 Hz, 2 H, OCH Me), 5.74 (br, 1 H, NHCMe ), 6.80 (br t, 1
2 2 2 2
2
3
(
NCH C H ), 52.11 and 52.89 (OMe), 59.13 (NCH), 61.71 (OCH Me),
H, CH NH), 7.50–7.63 (m, 3 H, H ), 7.64–7.72 (m, 1 H, H ).
2
2
5
2
2
Ar
Ar
115.11, 126.20, 127.29 (C ), 127.34, 130.17, 130.71, 131.82 (s, CH ),
q Ar
13
C NMR (CDCl , 126 MHz):  = 14.08 (OCH Me), 28.58 (CMe ), 44.11
3
2
3
1
36.80, 140.45 (C ), 157.08 (COOEt), 159.39 (C ), 161.41 and 163.36
q
q
(
CH NH), 51.52 (CMe ), 52.09 and 52.91 (OMe), 61.72 (OCH Me),
2
3
2
(
COOMe), 167.47 (C C=O), 170.52 (CHC=O).
q
1
1
1
15.03, 126.22, 127.20 (C ), 127.42, 130.19, 130.67, 131.69 (CH ),
q
A
r
+
HRMS (MALDI): m/z [M + H] calcd: 517.21806; found: 517.21857;
36.32 (C ), 140.31 (C ), 157.12 (COOEt), 159.14 (C ), 161.43 and
q
q
q
+
m/z [M – NHCH CH CH ] calcd: 458.14511; found: 458.14515.
63.41 (COOMe), 167.29 (CONHCMe ), 167.74 (CONHCH ).
2
2
3
3
2
+
Anal. Calcd for C26H32N O (516.55): C, 60.46; H, 6.24; N, 5.42. Found:
C, 60.41; H, 6.47; N, 5.23.
HRMS (MALDI): m/z [M + Na] calcd: 511.16870; found: 511.16799;
2
9
+
m/z [M + H] calcd: 489.18676; found: 489.18615.
Anal. Calcd for C24H28N O (488.49): C, 59.01; H, 5.78; N, 5.73. Found:
C, 58.80; H, 5.85; N, 5.72.
2
9
2
-Ethyl 3,4-Dimethyl 5-[2-({2-[(4-Bromophenyl)amino]-2-oxoeth-
yl}carbamoyl)phenyl]furan-2,3,4-tricarboxylate (9i)
Prepared from 3a (150 mg, 0.36 mmol) and 4-bromoaniline (76 mg,
0
.44 mmol). The crude yellow oil was purified by flash chromatogra-
phy (silica gel, EtOAc), then recrystallized (i-PrOH) to give 9i (142 mg,
7%) as a colorless solid; mp 177–178 °C.
6
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

L
Synthesis
M. Dobesch et al.
Paper
1
3
IR (ATR): 1183 (s), 1232 (s), 1534 (s), 1646 (m), 1711 (s), 3270 (br, w),
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 18.03 (CHMe), 28.66
3
2
–1
3397 cm (br, w).
(CH CH N ), 37.08 (NHCH ), 49.20 (CH CH N ), 49.35 (CHMe), 52.21
2 2 3 2 2 2 3
1
3
and 52.98 (OMe), 61.87 (OCH
127.37, 130.29, 130.82, 131.74 (CHAr), 136.55 (C
(COOEt), 159.12 (C ), 161.42 and 163.28 (COOMe), 167.63 (CHN-
HC=O), 171.79 (CH NHC=O).
2
Me), 115.09, 126.18, 127.00 (C
q
),
H NMR (CDCl , 500 MHz):  = 1.29 (t, J = 7.1 Hz, 3 H, OCH Me), 3.60
3
2
3
q
), 140.43 (C ), 157.09
q
(s, 3 H, OMe), 3.94 (s, 3 H, OMe), 4.16 (d, J = 5.5 Hz, 2 H, CH NH), 4.22
2
3
3
q
(q, J = 7.1 Hz, 2 H, OCH Me), 6.88 (t, J = 5.4 Hz, 1 H, CH NH), 7.34–
2
2
7
.44 (m, 4 H, H ), 7.55–7.72 (m, 4 H, H ), 8.68 (br, 1 H, CH CONH).
2
Ar
Ar
2
+
+
+
13
MS (MALDI): m/z = 568 [M + K] , 552 [M + Na] , 530 [M + H] .
C NMR (CDCl , 126 MHz):  = 13.97 (OCH Me), 45.14 (CH NH), 52.19
3
2
2
and 53.00 (OMe), 61.89 (OCH Me), 114.94 (C ), 116.62 (C ), 121.21
Anal. Calcd for C24H27N O (529.51): C, 54.44; H, 5.14; N, 13.23.
2
q
q
5
9
(
CH ), 126.06 (C ), 127.29 (C ), 127.42, 130.73, 130.88, 131.77,
Found: C, 54.40; H, 5.24; N, 13.18.
Ar
q
q
1
31.95 (CH ), 135.77, 136.93 (C ), 140.42 (C ), 156.87 (COOEt),
A
r
q
q
1
58.89 (C ), 161.45 and 163.22 (COOMe), 166.70 (CH NHC=O), 168.91
q
2
2-Ethyl 3,4-Dimethyl 5-(2-{[1-({3-[4,5-Bis(methoxycarbonyl)-1H-
1,2,3-triazol-1-yl]propyl}amino)-1-oxopropan-2-yl]carbam-
oyl}phenyl)furan-2,3,4-tricarboxylate (9l)
(CH CONH).
2
HRMS (MALDI): m/z [M(81Br, 13C1) + H]+ calcd: 590.06729; found:
81
+
5
90.06734; m/z [M( Br) + H] calcd: 589.06409; found: 589.06399;
A solution of N-(2-azidopropyl)carboxamide 9k (40 mg, 0.076 mmol)
m/z [M( Br, 13C1) + H]+ calcd: 588.06931; found: 588.06941; m/z
79
and DMAD (18 L, 0.15 mmol) in dry CHCl was heated at reflux tem-
3
79
+
[
M( Br) + H] calcd: 587.06597; found: 587.06601.
perature during 6 h. After cooling, the solvent was evaporated and the
residue was triturated with i-Pr O accompanied by ultrasonication for
Anal. Calcd for C26H23BrN O (587.38): C, 53.17; H, 3.95; N, 4.77.
Found: C, 52.99; H, 3.98; N, 4.78.
2
2
9
15 min. The resulting white solid was isolated by filtration and re-
crystallized (CHCl /PE) to give 9l (42 mg, 83%) as a colorless solid; mp
3
138–139 °C.
2-Ethyl 3,4-Dimethyl 5-[2-({2-[(4-Nitrophenyl)amino]-2-oxoeth-
IR (ATR): 1183 (s), 1224 (s), 1285 (m), 1635 (s), 1720 (s), 3304 cm–1
yl}carbamoyl)phenyl]furan-2,3,4-tricarboxylate (9j)
(
1
m).
Prepared from 3a (100 mg, 0.24 mmol) and 4-nitroaniline (50 mg,
3
0
.36 mmol) at r.t. for 40 h. A solution of the crude product in CH Cl
H NMR (CDCl , 500 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 1.39
3 2
2
2
3
3
was passed over a short column filled with silica gel to remove excess
-nitroaniline, then the product was eluted with acetone, isolated and
recrystallized (i-PrOH) to give 9j (93 mg, 70%) as a yellow solid; mp
89–191 °C.
IR (ATR): 1174 (s), 1231 (s), 1301 (s), 1333 (s), 1506 (s), 1717 (s), 3297
(d, J = 6.9 Hz, 3 H, CHMe), 2.15 (m , J = 6.3 Hz, 2 H, NCH CH ), 3.16–
3.32 (m, 2 H, CH NH), 3.70 (s, 3 H, OMe), 3.89–4.00 (m, 9 H, OMe),
2
4.33 (q, J = 7.1 Hz, 2 H, OCH Me), 4.50 (m , J = 7.3 Hz, 1 H, CHMe),
4.61 (t, J = 6.9 Hz, 2 H, NHCH CH CH ), 6.61 (d, J = 7.2 Hz, 1 H,
c
2
2
4
3
3
2
c
3
3
1
2 2 2
3
CHNH), 6.69 (mc, J = 5.8 Hz, 1 H, CH NH), 7.51–7.63 (m, 3 H, H ),
2
Ar
–1
7.65–7.71 (m, 1 H, HAr).
13C NMR (CDCl
, 126 MHz):  = 14.08 (OCH
(NHCH CH ), 36.11 (NHCH ), 47.92 (NHCH CH
52.28, 52.77, 53.02, 53.64 (OMe), 61.90 (OCH Me), 115.02, 126.14,
2
126.97 (C
1
cm (br, w).
1
3
3
2
Me), 18.13 (CHMe), 29.79
CH
H NMR (CDCl , 400 MHz):  = 1.23 (t, J = 7.1 Hz, 3 H, OCH Me), 3.61
3
2
3
2
2
2
2
2
2
), 49.48 (CHMe),
(s, 3 H, OMe), 3.91 (s, 3 H, OMe), 4.15 (q, J = 7.1 Hz, 2 H, OCH Me),
2
3
3
4
7
.26 (d, J = 5.0 Hz, 2 H, CH NH), 7.17 (m , J = 4.9 Hz, 1 H, CH NH),
2 c 2
.53–7.79 (m, 6 H, H ), 8.10 (d, J = 9.1 Hz, 2 H, o-H ), 9.61 (s, 1 H,
3
q
), 127.47 (CHAr), 129.88 (C
q
), 130.27, 130.83, 131.72 (CHAr),
Ar
Ar
36.54, 139.96, 140.36 (C ), 157.11 (COOEt), 159.12, 159.14 (C ,
CH CONH).
q
q
2
COOMe), 160.43, 161.43, 163.30 (COOMe), 167.64 (CHNHC=O),
72.03 (CH NHC=O).
13
C NMR (CDCl , 101 MHz):  = 13.90 (OCH Me), 45.18 (CH NH), 52.25
3
2
2
1
2
and 53.09 (OMe), 61.93 (OCH Me), 114.95 (C ), 119.05 (m-CH ),
2
q
Ar
+
HRMS (MALDI): m/z [M + Na] calcd: 694.19671; found: 694.19648;
m/z [M + H] calcd: 672.21476; found: 672.21472.
1
1
1
24.86 (o-CH ), 126.06 (C ), 127.14 (C ), 127.43, 130.97, 131.03,
Ar q q
+
32.04 (CH ), 135.48, 140.36, 143.32, 143.70 (C ), 156.80 (COOEt),
Ar
q
58.78 (C ), 161.39 and 163.14 (COOMe), 167.14 (CH CONH), 169.26
Anal. Calcd C30H33N O (671.62): C, 53.65; H, 4.95; N, 10.43. Found:
q
2
5
13
(
CH NHC=O).
C, 53.56; H, 4.93; N, 10.37.
2
+
HRMS (MALDI): m/z [M + Na] calcd: 576.12247; found: 576.12197.
2
-Ethyl 3,4-Dimethyl 5-[2-({1-[4-(Methoxycarbonyl)piperidin-1-
Anal. Calcd for C26H23N O (553.48): C, 56.42; H, 4.19; N, 7.59. Found:
3
11
yl]-1-oxopropan-2-yl}carbamoyl)phenyl]furan-2,3,4-tricarboxyl-
ate (9m)
C, 56.36; H, 4.29; N, 7.54.
A suspension of 3b (200 mg, 0.47 mmol) and methyl piperidine-4-
2
-Ethyl 3,4-Dimethyl 5-[2-({1-[(3-Azidopropyl)amino]-1-oxopro-
carboxylate hydrochloride (93 mg, 0.52 mmol) in anhyd CH Cl (5 mL)
2
2
pan-2-yl}carbamoyl)phenyl]furan-2,3,4-tricarboxylate (9k)
was treated with dry NEt (76 L, 0.55 mmol). After stirring at r.t. for
3
Prepared from 3b (100 mg, 0.23 mmol) and 2-azidopropan-1-amine
5
min, the clear yellow solution was worked up and the product was
(25 L, 0.25 mmol) at r.t. for 5 min. The yellow oil obtained after
recrystallized (i-PrOH/Et O) to give 9m (176 mg, 66%) as a colorless
2
workup was triturated with Et O (5 mL) in an ultrasonic bath for 5
min to give 9k (90 mg, 73%) as a colorless solid; mp 127–128 °C.
2
solid; mp 137–139 °C.
IR (KBr): 1178 (m), 1237 (s), 1625 (s), 1733 (vs), 3441 (v br, m).
IR (KBr): 1233 (s), 1637 (s), 1665 (s), 1722 (s), 1739 (s), 2103 (m),
1H NMR (CDCl
1
2
, 400 MHz):  = 1.25–1.38 (m, 6 H, CHMe, OCH
.57–1.83 (m, 2 H), 1.89–2.05 (m, 2 H), 2.50–2.64 (m, 1 H, CHCOOMe),
.80–3.00 (m, 1 H), 3.07–3.24 (m, 1 H), 3.64 and 3.65 (2 s, each 3 H, 2
Me),
214 (br, m), 3326 cm– (br, m).
1
3
2
3
1
H NMR (CDCl , 400 MHz):  = 1.30–1.40 (m, 6 H, OCH Me, CHMe),
3
2
3
1.74 (mc, J = 6.6 Hz, 2 H, CH CH N ), 3.21–3.38 (m, 4 H, NHCH ,
2
2
3
2
OMe), 3.75–3.91 (m, 1 H), 3.95 (s, 3 H, COOMe), 4.23–4.43 (m, 3 H,
3
CH CH N ), 3.70 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.35 (q, J = 7.1 Hz, 2
H, OCH Me), 4.48 (m , J = 6.9 Hz, 1 H, CHMe), 6.62 (t, J = 5.7 Hz, 1 H,
CH NH), 6.67 (d, J = 7.4 Hz, 1 H, CHNH), 7.50–7.68 (m, 4 H, H ).
3
2
2
3
COOCH Me, NC H), 4.84–4.96 (m, 1 H, CHMe), 7.02 and 7.12 (2 d, J =
2
x
3
3
2
c
7
.2 Hz, 2×0.5 H, NH), 7.49–7.62 (m, 3 H, H ), 7.62–7.71 (m, 1 H, H ).
A
r
A
r
3
2
Ar
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

M
Synthesis
M. Dobesch et al.
Paper
13
C NMR (CDCl , 126 MHz):  = 14.09 (OCH Me), 18.72 and 19.08
(Na SO ), and the solvent was evaporated. The residue was recrystal-
3
2
2
4
(
CHMe), 27.63, 27.67, 28.23, 28.33 (NCH CH ), 40.49 and 40.75 (CH-
lized (cyclohexane) to furnish Boc-L-Met-Gly-OMe (5.2 g, 81%) as a
colorless solid; mp 86–87 °C (Lit. 84–86 °C).
2
2
27
COOMe), 41.30, 41.56, 44.42, 44.66 (NCH ), 45.64 and 45.74 (CHMe),
2
5
1.88, 51.92, 52.09 (CHCOOMe, COOMe), 52.90 (COOMe), 61.67
IR (KBr): 1173 (m), 1208 (m), 1545 (m), 1660 (s), 1758 (m), 3288 (br,
m), 3425 cm (br, m).
(COOCH Me), 115.13, 126.31, 127.02, 127.06 (C ), 127.39, 127.43,
–1
2
q
1
1
1
29.95, 130.67, 131.62 (CH ), 136.91, 140.34 (C ), 157.11 (COOEt),
59.14, 159.16 (C ), 161.37 and 163.41 (COOMe), 166.43 (s, NHC=O),
70.13, 170.29 (CH CHCO), 174.17, 174.35 (CHCOOMe).
A
r
q
1
H NMR (CDCl , 500 MHz):  = 1.43 (s, 9 H, CMe ), 1.88–1.99 (m, 1 H,
3
3
A
q
A
B
B
NCHCH H ), 2.04–2.16 (m, 4 H, SMe, NCHCH H ), 2.58 (m , 2 H,
c
3
CH SMe), 3.74 (s, 3 H, OMe), 3.94–4.13 (m, 2 H, NCH ), 4.30–4.40 (m,
2
2
HRMS (MALDI): m/z [M + H]+ calcd for C28H33N O11: 573.20789;
found: 573.20806.
2
1 H, NHCH), 5.18–5.41 (m, 1 H, NHCH), 6.89 (br s, 1 H, CH NH).
2
13
C NMR (DMSO-d , 101 MHz):  = 14.78 (SMe), 28.38 (CMe ), 29.71
6
3
Anal. Calcd for C28H32N O (572.57): C, 58.74; H, 5.63; N, 4.89. Found:
C, 58.61; H, 5.62; N, 4.89.
2
11
(CH CH SMe), 31.85 (CH CH SMe), 40.77 (NCH ), 51.94 (OMe), 53.50
2 2 2 2 2
(NCH), 78.46 (CMe ), 155.58 (COOCMe ), 170.48 (COOMe), 172.64
3 3
(
CHC=O).
2
-Ethyl 3,4-Dimethyl 5-[2-({1-[(2-Methoxy-2-oxoethyl)amino]-1-
oxopropan-2-yl}carbamoyl)phenyl]furan-2,3,4-tricarboxylate
9n)
Anal. Calcd for C13H24N O S (320.40): C, 48.73; H, 7.55; N, 8.74; S,
1
2
5
0.01. Found: C, 48.77; H, 7.49; N, 8.76; S, 9.93.
(
A suspension of 3b (150 mg, 0.35 mmol) and methyl glycinate hydro-
2
-Ethyl 3,4-Dimethyl 5-(2-{[2-({1-[(2-Methoxy-2-oxoethyl)ami-
chloride (48 mg, 0.38 mmol) in anhyd CH Cl (5 mL) was treated with
2
2
no]-4-(methylthio)-1-oxobutan-2-yl}amino)-2-oxoethyl]carbam-
oyl}phenyl)furan-2,3,4-tricarboxylate (9o)
dry NEt (55 L, 0.40 mmol). After stirring at r.t. for 5 min, the clear
3
yellow solution was worked up according to the general procedure,
N-Boc-L-Met-Gly-OMe was kept in TFA at 65 °C for 12 h to obtain
methyl (L-methionyl)glycine. A solution of tetracycle 3a (287 mg, 0.69
mmol) in anhyd CH Cl (5 mL) was combined with a solution of L-
Met-Gly-OMe (152 mg, 0.69 mmol) in CH Cl (5 mL). After stirring at
r.t. for 10 min, the solvent was evaporated, and the remaining beige
and the product was recrystallized (CH Cl /Et O) to give 9n (123 mg,
2
2
2
68%) as a colorless solid; mp 155–156 °C.
2
2
IR (KBr): 1242 (s), 1543 (s), 1632 (s), 1650 (s), 1728 (s), 1753 (s), 3268
2
2
–
1
cm (s).
1
3
H NMR (CDCl , 500 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 1.39
foam was suspended in i-Pr O (5 mL). The suspension was heated at
3
2
2
3
(d, J = 7.0 Hz, 3 H, CHMe), 3.70 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 3.95
reflux and EtOAc was added dropwise. In this manner, byproducts
and impurities could be dissolved, whereas most of the desired prod-
uct remained as a colorless solid. It was isolated by filtration of the
hot suspension. An additional amount of the product was obtained by
evaporation of the mother liquor and repetition of the preceding
workup. The combined products were dried (50 °C/10 mbar) to fur-
nish pure 9o (307 mg, 70%) as a colorless solid; mp 147–149 °C.
IR (ATR): 1183 (s), 1231 (s), 1633 (s), 1716 (s), 3317 cm–1 (br, w).
3
3
(s, 3 H, OCH ), 4.01 (d, J = 5.4 Hz, 2 H, NHCH ), 4.34 (q, J = 7.1 Hz, 2 H,
3
2
3
3
OCH Me), 4.59 (m , J = 7.0 Hz, 1 H, CHMe), 6.63 (d, J = 7.4 Hz, 1 H,
2
c
NHCH), 6.78 (br t, 1 H, NHCH ), 7.51–7.61 (m, 3 H, H ), 7.63–7.69 (m,
2
Ar
1
H, HAr).
–3
13
C NMR (CDCl , 126 MHz):  = 14.06 (OCH Me), 17.81 (CHMe), 41.14
3
2
(
(
(
CH NH), 49.06 (CHMe), 52.22 and 52.31 (OMe), 52.97 (OMe), 61.85
2
OCH Me), 115.10, 126.13, 126.94 (C ), 127.48, 130.23, 130.80, 131.66
2
q
CH ), 136.57 (C ), 140.42 (C ), 157.10 (COOEt), 159.06 (C ), 161.43
1
3
Ar
q
q
q
H NMR (CDCl , 400 MHz):  = 1.34 (t, J = 7.1 Hz, 3 H, OCH Me), 1.96–
3 2
and 163.32 (COOMe), 167.64 (CHNHC=O), 170.01 (CH COOMe),
2
2.18 (m, 5 H, CH CH SMe), 2.52–2.66 (m, 2 H, CH CH SMe), 3.68–3.73
2
2
2
2
172.03 (CHC=O).
(m, 6 H, CH COOMe, COOMe), 3.96 (s, 3 H, OMe), 3.97–4.05 (m, 4 H,
2
+
+
+
3
MS (CI): m/z = 519 [M + H] , 518 [M] , 430 [M – NHCH COOCH ] , 359
NCH ), 4.34 (q, J = 7.1 Hz, 2 H, OCH Me), 4.63–4.72 (m, 1 H, NHCH),
6.82–6.89 (m, 1 H, C CONH), 6.93–7.02 (m, 2 H, NHCHCONH), 7.52–
2
3
2
2
+
[
M – NHCHR ] .
2
q
7
.65 (m, 3 H, H ), 7.67–7.73 (m, 1 H, H ).
Anal. Calcd for C24H26N O (518.48): C, 55.60; H, 5.05; N, 5.40. Found:
C, 55.79; H, 4.99; N, 5.40.
A
r
A
r
2
11
13
C NMR (CDCl , 126 MHz):  = 14.07 (OCH Me), 15.16 (SMe), 30.10
3 2
(
CH CH SMe), 30.67 (CH CH SMe), 41.12 (CH COOMe), 43.74
2 2 2 2 2
(
CH CONH), 52.22 (NHCH), 52.28 (COOMe, CH COOMe), 52.96
2 2
2
-Ethyl 3,4-Dimethyl 5-(2-{[2-({1-[(2-Methoxy-2-oxoethyl)ami-
(COOMe), 61.87 (COOCH Me), 115.15, 126.11, 127.08 (C ), 127.62,
no]-4-(methylthio)-1-oxobutan-2-yl}amino)-2-oxoethyl]carbam-
oyl}phenyl)furan-2,3,4-tricarboxylate (9o)
2
q
1
1
30.29, 130.74, 131.73 (CH ), 136.17, 140.40 (C ), 157.16 (COOEt),
Ar q
58.95 (C ), 161.52 and 163.38 (COOMe), 168.22 (C CONH), 168.77
q
q
(
CH CONH), 170.03 (s, CH COOMe), 171.19 (s, CHC=O).
2
2
N-[(tert-Butoxycarbonyl)-L-methionyl]glycine Methyl Ester (Boc-
L-Met-Gly-OMe)
HRMS (MALDI): m/z [M + K]+ calcd for C28
found: 674.14168; m/z [M
658.16772; found: 658.16672; m/z [M + H] calcd for C28
6
H
N
O
12SK: 674.14165;
33
3
+
+
Na] calcd for C28H33N O12SNa:
Syntheses by peptide coupling of Boc-L-Met-OH and Gly-OMe using
3
+
26
27
H
34
N
3
O
12S:
DCC or isobutyl chloroformate as activating reagents have been
published. The use of CDI as coupling reagent is described herein.
36.18577; found: 636.18543.
Anal. Calcd for C28H33N O12S (635.64): C, 52.91; H, 5.23; N, 6.61; S,
A
solution of N-(tert-butoxycarbonyl)-L-methionine (5.00 g, 20
3
5.04. Found: C, 52.90; H, 5.18; N, 6.60; S, 5.04.
mmol) in dry CH Cl (200 mL) was cooled at 0 °C, CDI (4.40 g, 27
2
2
mmol) was added in portions, and the mixture was stirred overnight.
Methyl glycinate hydrochloride (2.60 g, 21 mmol) followed by NEt (3
X-ray Structure Determination of exo-3c
3
mL, 22 mmol) was added. The solution was stirred for 8 h, then dilut-
ed with CH Cl (100 mL). After extraction with dilute 1 M aq HCl (100
mL) and water (2 × 100 mL), the organic layer was separated, dried
Suitable crystals were obtained by crystallization (CH Cl /pentane) by
2
2
2
2
the vapor diffusion method. Data collection was performed with an
Oxford Diffraction instrument (SuperNova, Dual Source, Atlas CCD, Cu
K radiation). Software for structure solution and refinement:
28a
28b
29
SHELXS97
and SHELXL-2014.
Molecule plot: ORTEP. CCDC-
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

N
Synthesis
M. Dobesch et al.
Paper
1
987125 contains the supplementary crystallographic data for this
(13) (a) Hodgson, D. M.; Glen, R.; Grant, G. H.; Redgrave, A. J. J. Org.
Chem. 2003, 68, 581. (b) Shimada, N.; Hanari, T.; Kurosaki, Y.;
Takeda, K.; Anada, M.; Nambu, H.; Shiro, M.; Hashimoto, S.
J. Org. Chem. 2010, 75, 6039.
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
Selected crystallographic data: C23H23NO (457.42); monoclinic space
group P2 /c, a = 12.2649(2), b = 19.0631(2), c = 9.6849(1) Å,  =
1
9
(
14) (a) Enßle, M.; Buck, S.; Werz, R.; Maas, G. ARKIVOC 2012, (iii),
149. (b) Enßle, M.; Buck, S.; Werz, R.; Maas, G. Beilstein J. Org.
Chem. 2012, 8, 433.
1
3
–3
04.817(1)°; V = 2189.10(4) Å ; Z = 4, 
= 1.388 g cm ,  = 0.91
calcd
–1
mm . R = 0.0417 (3483 reflections with I > 2(I)), wR2 = 0.1112 (all
864 data).
(15) Nakhla, M. C.; Lee, C.-W.; Wood, J. L. Org. Lett. 2015, 17, 5760.
(16) Padwa, A.; Zhi, L.; Fryxell, G. E. J. Org. Chem. 1991, 56, 1077.
(17) (a) König, B. In Science of Synthesis, Vol. 9; Maas, G., Ed.; Thieme:
Stuttgart, 2000, 183–285. (b) Keay, B. A. Chem. Soc. Rev. 1999,
3
Acknowledgment
28, 209.
(
18) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084. (b) Moran, W. J.; Rodgriuez, A. Org.
Prep. Proced. Int. 2012, 44, 103. (c) Kirsch, S. F. Org. Biomol.
Chem. 2006, 4, 2076. (d) Brown, R. C. D. Angew. Chem. Int. Ed.
This work was supported by the University of Ulm. We thank Tobias
Steudner for experimental assistance, Dr. M. Wunderlin (Institute of
Organic Chemistry II) for the mass spectra, E. Kaltenegger-Zeisberger
for the DSC measurements, and B. Müller for the XRD data collection.
2005, 44, 850.
(
19) Selected recent examples: (a) Liu, W.; Jiang, H.; Zhang, M.; Qi, C.
J. Org. Chem. 2010, 75, 966. (b) Yang, Y.; Jao, J.; Zhang, Y. Org.
Lett. 2013, 15, 3206. (c) Palisse, A.; Kirsch, S. F. Eur. J. Org. Chem.
2014, 7095. (d) Schmidt, D.; Malkar, C. C.; Beifuss, U. Org. Lett.
2014, 16, 4862. (e) Wu, J.; Yoshikai, N. Angew. Chem. Int. Ed.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707897.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
2015, 54, 11107. (f) Manna, S.; Antonchick, A. P. Org. Lett. 2015,
17, 4300.
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©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N